N-acyl-2-aryl cyclopropylmethylamine derivatives as melatonergics

ABSTRACT

Certain N-acyl 2-aryl cyclopropylmethylamine derivatives are useful as melatonergic agents.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional application of application U.S. Ser. No. 08/644,087filed May 9, 1996 now U.S. Pat. No. 5,753,709, which is acontinuation-in-part of U.S. Ser. No. 08/486,633 filed Jun. 7, 1995, nowabandoned.

BACKGROUND OF THE INVENTION

The invention pertains to novel N-acyl 2-arylcyclopropylmethylaminederivatives having drug and bio-affecting properties, to theirpreparation, to pharmaceutical formulations containing them and tomethods of using them. These compounds possess melatonergic propertiesthat should make them useful in treating certain medical disorders.

Melatonin (i; N-acetyl-5-methoxytryptamine) is a hormone which issynthesized and secreted primarily by the pineal gland. In mammals,melatonin levels show a cyclical, circadian pattern, with highest levelsoccurring during the dark period of a circadian lightdark cycle.Melatonin is involved in the transduction of photoperiodic informationand appears to modulate a variety of neural and endocrine functions invertebrates, including the regulation of reproduction, body weight andmetabolism in photoperiodic mammals, the control of circadian rhythmsand the modulation of retinal physiology. ##STR1##

Recent evidence demonstrates that melatonin exerts its biologicaleffects through specific receptors. Use of the biologically active,radiolabelled agonist ¹²⁵ I!-2-iodomelatonin has led to theidentification of high affinity melatonin receptors in the centralnervous systems (CNS) of a variety of species. The sequence of one suchhigh affinity melatonin receptor, cloned from frog melanocytes, has beenreported. In mammalian brain, autoradiographic studies have localizedthe distribution of melatonin receptors to a few specific structures.

Although there are significant differences in melatonin receptordistribution even between closely related species, in general thehighest binding site density occurs in discrete nuclei of thehypothalamus. In humans, specific ¹²⁵ I!-2-iodomelatonin binding withinthe hypothalamus is completely localized to the suprachiasmatic nucleus,strongly suggesting that melatonin receptors are located within thehuman biological clock.

Exogenous melatonin administration has been found to synchronizecircadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229,1986). In humans, administration of melatonin has been used to treatjet-lag related sleep disturbances, considered to be caused bydesynchronization of circadian rhythms (Arendt, et al., Br. Med. J.292:1170, 1986). Further, the use of a single dose of melatonin toinduce sleep in humans has been claimed by Wurtman in InternationalPatent Application WO 94/07487.

Melatonin binding sites have been found in diverse tissues of thebody--i.e., in the retina, superchiasmatic nucleus, spleen, etc. Thismeans that melatonin exerts multiple physiological effects and is nothighly selective. The potential for side effects with melatonin use islarge. Melatonin agonists should be more selective than melatonin andhave fewer side effects. Suitable melatonin agonists could overcomemelatonin's drawbacks, resulting in products having more predictableand, possibly, sustained activity.

Melatonin agonists should be particularly useful for the treatment ofchronobiological disorders. They would also be useful for the furtherstudy of melatonin receptor interactions as well as in the treatment ofconditions affected by melatonin activity, such as depression,work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer,immune disorders, neuroendorine disorders, and a variety of sleepdisorders.

Aside from simple indole derivatives of melatonin itself, various amidestructures have been prepared and their use as melatonin ligandsdisclosed. In general these amide structures can be represented as:##STR2## wherein Z is an aryl or heteroaryl system attached by a twocarbon chain to the amide group. Some specific examples follow.

Yous, et al. in European Patent Application EPA 527 687A disclose, asmelatonin ligands, ethylamines having cyclic substituents, 1, ##STR3##wherein Ar' is, inter alias, a substituted or unsubstituted benzob!thiophen-3-yl, benzimidazol-1-yl, benzo b!furan-3-yl,1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical;R₁ is, inter alia, an alkyl or cycloalkyl group; and R₂ is hydrogen orlower alkyl.

Langlois, et al., in Australian Patent Application AU-A48729/93 disclosearylalkyl(thio)amides 2 as melatonergic ligands, ##STR4## wherein R₁ ishydrogen or lower alkyl; R₂ is hydrogen, halogen, or lower alkyl; R₃ andR₄ are identical or different groups including, inter alia, hydrogen,halogen, or lower alkyl; R₅ is hydrogen or lower alkyl; X is sulfur oroxygen and R₇ is, inter alia, lower alkyl or alkenyl.

However, these references do not teach or suggest the novel melatonergicaryl cyclopropylmethylamine derivatives of the present invention.

A number of compounds containing structural elements common to thecompounds of the present invention have been disclosed, althoughmelatonergic properties have not been claimed for any the compoundswithin these disclosures.

Matsuda, et al., in international patent application W095/22521 disclose1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides 3 asN-methyl-D-aspartate (NMDA) receptor antagonists, wherein R₁ represents,inter alia, a C₁ -C₅ linear saturated aliphatic, a C₁ -C₅ linearunsaturated aliphatic, a branched aliphatic, or a phenyl group which maybe substituted with one to three substituents selected independentlyfrom the group consisting of halogen, C₁ -C₄ alkyl, nitro, amino,hydroxy, and C₁ -C₄ alkoxy. ##STR5##

The 1,2-diarylcyclopropane derivatives of type 4 are disclosed in NE6701256 as having CNS stimulant properties, ##STR6## Ar₁ and Ar₂ areindependently and optionally substituted phenyl; R₁ is inter aliahydrogen, lower alkyl or acyl; R₂ is inter alia alkyl, cycloalkyl oraralkyl.

SUMMARY OF THE INVENTION

The present invention is concerned with compounds of Formula I, whichpossess melatonergic properties and thus have utility in the treatmentof conditions affected by melatonin activity: ##STR7## wherein: X ishalogen, hydrogen, C₁₋₄ alkyl or OR₅, wherein R₅ is hydrogen, C₁₋₄perfluoroalkyl, C₁₋₄ fluoroalkyl, C₁₋₄ perdeuteroalkyl, C₁₋₂₀ alkyl,C₄₋₂₀ alkcycloalkyl, C₂₋₂₀ carbonitriloalkyl, C₃₋₂₂ carboalkoxyalkyl,C₃₋₂₀ alkenyl, C₃₋₂₀ alkynyl, C₉₋₂₀ aralkyl, C₉₋₂₀ aralkenyl, C₉₋₂₀aralkynyl, C₂₋₂₀ hydroxyalkyl, C₈₋₂₀ aryloxyalkyl, C₇₋₂₀ pyridylalkyl,or C₆₋₂₀ pyrrylalkyl;

Y is hydrogen or halogen;

Z is hydrogen, halogen, cyano, aryl, C₇₋₂₀ aralkyl, C₈₋₂₀ arylkynyl, orC₂₋₂₀ alkamido;

R, in both cases, is hydrogen, halogen, or C₁₋₄ alkyl;

G is a divalent methylene, ethylene, or C₁₋₄ alkmethylene moiety;

R₁ is hydrogen, C₁₋₄ alkyl or benzyl; and

R₂ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₄ alkoxyalkyl, C₁₋₄trifluoromethylalkyl, C₂₋₈ alkylthioalkyl or NR₃ R₄, wherein R₃ and R₄are independently selected from hydrogen and C₁₋₄ alkyl, but R₃ and R₄cannot both be hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

This invention deals with compounds of Formula I, their preparation andtheir use in methods and compositions for treating certain conditions.

Formula I is: ##STR8## wherein: X is halogen, hydrogen, C₁₋₄ alkyl orOR₅, wherein R₅ is hydrogen, C₁₋₄ perfluoroalkyl, C₁₋₄ fluoroalkyl, C₁₋₄perdeuteroalkyl, C₁₋₂₀ alkyl, C₄₋₂₀ alkcycloalkyl, C₂₋₂₀carbonitriloalkyl, C₃₋₂₂ carboalkoxyalkyl, C₃₋₂₀ alkenyl, C₃₋₂₀ alkynyl,C₉₋₂₀ aralkyl, C₉₋₂₀ aralkenyl, C₉₋₂₀ aralkynyl, C₂₋₂₀ hydroxyalkyl,C₈₋₂₀ aryloxyalkyl, C₇₋₂₀ pyridylalkyl, or C₆₋₂₀ pyrrylalkyl;

Y is hydrogen or halogen;

Z is hydrogen, halogen, cyano, aryl, C₇₋₂₀ aralkyl, C₈₋₂₀ arylkynyl, orC₂₋₂₀ alkamido;

R, in both cases, is hydrogen, halogen, or C₁₋₄ alkyl;

G is a divalent methylene, ethylene, or C₁₋₄ alkmethylene moiety;

R₁ is hydrogen, C₁₋₄ alkyl or benzyl; and

R₂ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₄ alkoxyalkyl, C₁₋₄trifluoromethylalkyl, C₂₋₈ alkylthioalkyl or NR₃ R₄, wherein R₃ and R₄are independently selected from hydrogen and C₁₋₄ alkyl, but R₃ and R₄cannot both be hydrogen.

It is to be understood that, as used herein, "halogen" denotes fluorine,chlorine, bromine and iodine; the term "alkyl" refers to straight andbranched chain saturated hydrocarbon radicals; "fluoroalkyl" refers tostraight and branched chain monofluorosubstituted saturated hydrocarbonradicals; "alkenyl" refers to straight and branched hydrocarbon radicalscontaining a carbon-carbon double bond; "cycloalkyl" refers to saturatedcyclic hydrocarbon radicals; "alkoxy" denotes an alkyl radical connectedto a molecule via an oxygen atom; "alkylthioalkyl" refers to an alkylradical linked to another via a sulfur atom; "aryloxyalkyl" refers to analkyl radical linked to an optionally substituted phenyl group via anoxygen atom; "alkcycloalkyl" refers to an alkyl radical linked to asaturated cyclic hydrocarbon radical; "carbonitriloalkyl" refers to analkyl radical linked to a nitrilo radical via a carbon atom;"carboalkoxyalkyl" refers to an alkyl radical linked directly to acarboalkoxy radical; "hydroxyalkyl" refers to an alkyl radical linked toa hydrogen atom via an oxygen atom; "pyridylalkyl" refers to a pyridylradical linked directly to the terminal carbon of an alkyl radical;"pyrrylalkyl " refers to a pyrryl radical linked directly to theterminal carbon of an alkyl radical; "trifluoromethylalkyl" refers to atrifluoro-substituted methyl group linked directly to an alkyl radical;"perfluoralkyl" refers to straight and branched chain saturatedfluorocarbon radicals; "perdeuteroalkyl" refers to straight and branchedchain saturated deuterocarbon radicals; "cyano" refers to a radicalcontaining a carbon-nitrogen triple bond; "alkynyl" refers to straightand branched hydrocarbon radicals containing a carbon-carbon triplebond; "aralkyl", "aralkenyl", and "aralkynyl" (or "arylalkyl","arylalkenyl" and "arylalkynyl", respectively) refer to radicals inwhich an optionally substituted phenyl group is appended to the terminalcarbon of an alkyl, alkenyl or alkynyl radical respectively; "alkamido"(or "alkylamido") refers to --NC(O)-alkyl groups containing the statednumber of carbon atoms; "alkmethylene" (or "alkylmethylene") refers toan alkyl radical attached directly to a methene radical. "Benzyl" or"Bn" refers to the phenylmethyl group, --CH2-phenyl. Phenyl groups, whenpresent, bear substituents selected from hydrogen, halogen,trifluoromethyl and C₁₋₄ alkoxy moieties.

Numbers recited in subscripts immediately following "C" denote thenumber of carbon atoms in the moiety.

Based upon biological tests, the following Formula I compounds arepreferred. All have binding affinities for the human melatonin receptorwith IC₅₀ values of 600 nM or less.

Preferred compounds of formula I are those wherein R₁ is hydrogen, R₂ isC₁₋₄ alkyl, Y and Z are independently hydrogen or halogen, and X is OR₅,wherein R₅ is C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₃₋₂₀ alkynyl, and C₉₋₂₀aralkyl, aralkenyl or aralkynyl. It is preferred that R₂ be devoid of O,N and S atoms. It is highly preferred that R₂ be C₁₋₄ alkyl.

Preferred compounds of the present invention include those in thefollowing list:

(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!butanamide;

(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!-2-methoxyacetamide;

(+)-(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!-methyl!butanamide;

(-)-(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!butanamide;

(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!propanamide;

(trans)-N- 2-(4Chloro-3-methoxyphenyl)cyclopropyl!methyl!butanamnide;

(-)-(trans)-N-2-(3-Methoxyphenyl)cyclopropyl!methyl!-2-methylpropanamide;

(trans)-N- 2- 3-(6-Phenylhexyl)oxy!phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2-(2-Bromo-5-methoxyphenyl)cyclopropyl!methyl!butanamide;

(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!acetamide;

(-)-(trans)-N-2-(2,4-Dibromo-5-methoxyphenyl)-cyclopropyl!methyl!butanamide;

(trans)-N- 2-(2-Iodo-5-methoxyphenyl)cyclopropyl!methyl!butanamide;

(-)-(trans)-N- 2-(2-Iodo-5-methoxyphenyl)cyclopropyl!methyl!butanamide;

(trans)-N- 2- 3-(Heptyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- 3-(2-Propenyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- 3-(7-Phenylheptyl)oxy!phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2-(3- (Ethoxyphenyl)cyclopropyl!methyl!butanamide;

(trans)-N- 2- (3-Octyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- 3-(Nonyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- (3-Decyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- (3-Undecyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- (3-Dodecyloxy)phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- 3-(2-Phenylethyl)oxy!phenyl!cyclopropyl!methyl!butanamide;

(trans)-N- 2- 3-3-(3-Methoxyphenyl)propoxy!phenyl!cyclopropyl!methyl!butanamide;

(-)-(trans)-N-2-(5-Methoxy-2-(phenylethynyl)phenyl)cycloprop-1-yl!methyl!butanainide;

(trans)-N-3-(3-Methoxyphenyl)-2,2-difluoro-1-cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N- 2-(3-Methoxyphenyl)cycloprop-1-yl!methyl!cyclopropanecarboxamide;

(-)-(trans)-N- 2- 3-3-(3-Methoxyphenyl)propoxylphenyl!cycloprop-1-yl)-methyl!butanamide;

(-)-(trans)-N- 2-(3-Methoxyphenyl)cycloprop-1-yl!methyl!-N'-methyl urea;

(-)-(trans)-N- 2-(3-Methoxyphenyl)cycloprop-1-yl!methyl!propanamide;

(-)-(trans)-N- 2-(3-Methoxyphenyl)cycloprop-1-yl!methyl!acetamide;

(-)-(trans)-3,3,3-Trifluoro-N-2-(3-methoxyphenyl)cycloprop-1-yl!methyl!propanamide;

(trans)-N- 2- 3- (3-,7,11-Trimethyldodeca-2,6,10-trien-1-yl)oxy!phenyl!-cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-(4-Phenylbut-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-(5-Phenylpent-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(3-Trideuteromethoxyphenyl)cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-(3Cyclohexylprop-1-yl)oxylphenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-(3Cyclopentylprop-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3- 2-3-(Trifluoromethyl)phenyl!ethoxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-2-(3-Methoxyphenyl)cycloprop-1-yl!methoxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(4Chloro-3-methoxyphenyl)cyclopropyl!methyl!butanamide;

(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!-2-methylthioacetamide;

(trans)-N- ² - 3-3-(3-Methoxyphenyl)propoxy!phenyl!cyclopropyl!methyl!butanamide;

(-)-(trans)-N-2-(4-Iodo-3-methoxyphenyl)cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N-2-(5-Methoxy-2-(phenylethyl)phenyl)cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N- 2-(4-Methoxy- 1,1 '-biphenyl! -²yl-cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N- 2- 4-Methoxy4'-(trifluoromethyl)1,1'-biphenyl!-2yl!-cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(3-Bromophenyl)cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(3-Bromophenyl)cycloprop-1-yl!methyl!acetamide;

(trans)-N- 2-(3-Bromophenyl)cycloprop-1-yl!methyl!propanamide;

(-)-(trans)-N- 2- 2-Iodo-5-3-(3-methoxyphenyl)propoxy!phenyl!cycloprop-1-yl) methyl!butanamide;

(trans)-N- 2- 3(3-Phenylprop-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3(3-Phenoxyprop-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3(3-Dimethylocta-2,6-dien-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-3-(5-Methylhexyloxy)phenyl!cycloprop-1-yl!methyl!butanaride;

(trans)-N- 2-3-(4-Methyl-3-penten-1-yloxy)phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-(3Cyclohexylbut-1-yl)oxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3- 2-2-(Trifluoromethyl)phenyl!ethoxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3-2-(3-Fluorophenyl)ethoxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-3-(3-(4-Methoxyphenyl)propoxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3- 2-(2-Fluorophenyl)ethoxy!phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- 3- 2-(2-Methoxyphenyl)ethoxy!phenyl!cycloprop-1-yl!methyl!butanarnide;

(-)-(trans)-N- 2-(3-Fluorophenyl)cyclopropyl!methyl!butanamide;

(-)-(trans)-N-2-(3-Fluorophenyl)cycloprop-1-yl!methyl!-2-methylpropanamide;

(-)-(trans)-N-2-(2-Bromo-5-fluorophenyl)cycloprop-1-yl!methyl!butanarnide;

(-)-(trans)-N-2-(4-Bromo-3-fluorophenyl)cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N-2-(5-Fluoro-2-iodophenyl)cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N-2-(3-Fluoro4-iodophenyl)cycloprop-1-yl!methyl!butanarnide;

(trans)-N-3-(3-Methoxyphenyl)-2,2-difluoro-1-cycloprop-1-yl!methyl!butanamide;

(trans)-N-3-(3-Methoxyphenyl)-2,2-difluoro-1-cycloprop-1-yl!methyl!-2-methylpropanamide;

(trans)-N- 2-(3-Bromophenyl)cycloprop-1-yl!methyl!butanarnide;

(trans)-N- 2-(3-Bromophenyl)cycloprop-1-yl!methyl!acetamide;

(trans)-N- 2-(3-Methylphenyl)cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(3-Bromophenyl)cycloprop-1-yl!methyl!propanamide;

(trans)-N- 2-(3-Methylphenyl)cycloprop-1-yl!methyl!-2-methylpropanamide;

(trans)-N- 2-(3-Methylphenyl)cycloprop-1-yl!methyl!acetamide;

(trans)-N- 2-(3-Chlorophenyl)cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(3-Chlorophenyl)cycloprop-1-yl!methyl!propanamide;

(trans)-N- 2-(3-Chlorophenyl)cycloprop-1-yl!methyl!acetamide;

(trans)-N- 2-(3-Chlorophenyl)cycloprop-1-yl!methyl!cyclopropanecarboxamide;

(trans)-N- 2-(2,5-Difluorophenyl)cycloprop-1-yl!methyl!acetamide;

(trans)-N- 2-(2,5-Difluorophenyl)cycloprop-1-yl!methyl!propanamide;

(trans)-N- 2-(2,5-Difluorophenyl)cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(2,5-Difluorophenyl)cycloprop-1-yl!methyl!cyclopropanecarboxamide;

(trans)-N- 2-3-(Pentafluoroethyl)phenyl!cycloprop-1-yl!methyl!butanamide;

(-)-(trans)-N- (2-Phenylcycloprop-1-yl)methyl!butanamide;

(trans)-N- (2-Phenylcycloprop-1-yl) methyl!acetamide;

(trans)-N- (2-Phenylcycloprop-1-yl) methyl!butanamide;

(trans)-N- 2- (3-Ethylphenyl) cycloprop-1-yl!methyl!acetamide;

(trans)-N- 2- (3-Ethylphenyl) cycloprop-1-yl!methyl!propanamide;

(trans)-N- 2- (3-Ethylphenyl) cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2- (3-Ethylphenyl)cycloprop-1-yl!methyl!cyclopropanecarboxamide;

(trans)-N- 2-3-(Trifluoromethyl)phenyl!cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-3-(Trifluoromethyl)phenyl!cycloprop-1-yl!methyl!-2-methylpropanamide;

(-)-(trans)-N-2-(2-Bromo-5-fluorophenyl)cycloprop-1-yl!methyl!butanamide;

(trans)-N- 2-(3-Methylphenyl)cycloprop-1-yl!methyl!butanamide; and(trans)-N- 2- (3-Ethylphenyt)cycloprop-1-yl!methyl!butanamide.

The compounds of Formula I can be prepared as depicted in the followingschemes (Processes 1-8). The groups R, R₁, R₂,R₃,R₄ X, Y, Z, G and R₅are as defined herein above.

Process 1 ##STR9##

In the resultant Formula I compounds, R₁ and R are H, G is methylene,and the other substitutents are as defined above.

Process 2 ##STR10##

Using Process 2, the R₂ group in the final formula I compound is alkyl,NHR₃, or NR₃ R₄ (as defined above). G is methylene; R₁ and R are H.

Process 3 ##STR11##

In Formula I compounds made using Process 3, R₁, R, Y and Z are all H,and G is methylene.

Processes 4,5 ##STR12##

When using Process 4, the Formula I compounds made are those in which Gis methylene; Y, R₁, and R are H, and Z is Br or I. Formula I compoundsproduced via Process 5 are those wherein Y and Z are both Br or I, G ismethylene, and R₁ and R are H.

Process 6 ##STR13##

Via Process 6, the Formula I compounds made are those in which R₁ isC₁₋₄ alkyl or benzyl, G is methylene, R is H, and R₂, X, Y, Z are asdefined above.

Processes 7,8 ##STR14##

In Processes 7 and 8, the final Formula I compounds are those in which Gis methylene, X is OR₅, R₁ and R are H, and Y, Z, R₂ and R₅ have thedefinitions given above.

Process 9 ##STR15##

Via Process 9, the formula I compounds wherein X is OCH₃, G ismethylene, Z is phenylalkyne or hydrocinnamyl, and R₁, R and Y arehydrogen are produced.

Processes 10, 11 ##STR16##

Via Process 10, the formula I compounds wherein X is OCH₃, G ismethylene, Z is cyano, and R₁, R and Y are hydrogen are produced. ViaProcess 11, the formula I compounds wherein X is OCH₃, G is methylene, Zis phenyl, and R₁, R and Y are hydrogen are produced.

Process 12 ##STR17##

Via Process 12, the formula I compounds wherein X is OCH₃, R isfluorine, G is methylene, and Z, R₁, and Y are hydrogen are produced.

Process 13 ##STR18##

Via Process 13, the formula I compounds in which X is OCH₃, Z isalkamido, G is methylene, and R, R₁, and Y are hydrogen are produced.

Process 14 ##STR19##

Via Process 14, the formula I compounds wherein X is OCH₃, G isalkmethylene, and R, R₁, Z, and Y are hydrogen are produced.

Process 15 ##STR20##

Via Process 15, the formula I compounds wherein X is 2-hydroxyethyl, Gis methylene, and R, R₁, Z, and Y are hydrogen are produced.

Process 16 ##STR21##

Via Process 16, the formula I compounds wherein X is OCH₃, G isethylene, and R, R₁, Z, and Y are hydrogen are produced.

Process 17 ##STR22##

Via Process 17, the formula I compounds wherein X is OCH₃, G ismethylene, R is methyl, and R₁, Z, and Y are hydrogen are produced.

Unless stated otherwise, all substituents on the Formula I compoundsproduced via Processes 1-17 may have any of the definitions recited inthe first discussion of Formula I herein.

The preparation of Compounds of Formula I involves the following stepsdescribed for each of Processes 1-17:

Process 1 (Reactions a-d)

(i) Treatment of commercially available aldehydes of Formula II withsodium hydride and cyanomethylphosphonate, followed by cyclopropanationwith dimethyloxosulphonium methylide gave intermediate cyclopropanenitrites of Formula III.

(ii) Catalytic reduction of nitrites III by hydrogen in the presence ofplatinum oxide, followed by acylation of the resultant amine with anappropriate acyl chloride, gave compounds of Formula I, wherein R₁ ishydrogen.

Process 2 (Reactions a-g)

(i) Treatment of commercially available cinnamic acids of Formula IVwith refluxing thionyl chloride, followed by acylation withN,O-dimethyl-hydroxylamine hydrochloride in the presence of pyridinegave unsaturated N-methyl,N-methoxy amides which were cyclopropanatedwith dimethyloxophosphonium methylide to give intermediates of FormulaV.

(ii) Reduction of amides V with lithium aluminum hydride gave aldehydesof formula VI.

(iii) Aldehydes VI were converted to oximes with hydroxylaminehydrochloride and sodium hydroxide, and reduced with lithium aluminumhydride to give amines of Formula VII.

(iv) Compounds of formula VII were acylated with appropriate acylatingagents, such as acyl chlorides, carbamoyl chlorides, or isocyanates togive compounds of Formula I, wherein R₁ is hydrogen, and R₂ is alkyl,NR₃ R₄, or NHR₃ as defined previously.

Process 3 (Reactions a-e)

(i) Reduction of the known homochiral sultams VIII with lithium aluminumhydride produced alcohols IX as single enantiomers.

(ii) Conversion of alcohols IX to the corresponding methanesulfonateesters with methanesulfonyl chloride and triethylamine, followed byazide formation with sodium azide in dimethylformamide, and lithiumaluminum hydride reduction gave enantiopure amines of Formula X.

(iii) Amines X were acylated with appropriate acyl chlorides to givecompounds of Formula I wherein R₁ is hydrogen and Y and Z are hydrogen.

Process 4

Amides XI, produced by Processes I, II or III, were treated withthallium (III) acetate and 1 equivalent of bromine or iodine to givecompounds of Formula I wherein Y is hydrogen, Z is bromine or iodine,and R₁ is hydrogen.

Process 5

Amides XI, produced by Processes I, II or III, were treated withthallium (III) acetate and 2 or more equivalents of bromine or iodine togive compounds of Formula I wherein Y is equal to Z is equal to bromineor iodine, and R₁ is hydrogen.

Process 6

Amides XII, produced by Processes I, II or III, were treated with sodiumhydride and an appropriate alkyl or benzylhalide to give compounds ofFormula I wherein R₁ is C₁₋₄ alkyl or benzyl.

Process 7

(i) Amides XIII, produced by Processes I, I or III, were treated withboron tribromide to produce compounds of Formula XIV.

(ii) Amides XIV were treated with base and the resultant alkoxides werealkylated with appropriate alkyl iodides or alkyl bromides to producecompounds of Formula I wherein X is OR₅ and R₁ is hydrogen.

Process 8

(i) Amides XIII, produced by Processes I, II or III, were treated withboron tribromide to produce compounds of Formula XIV.

(ii) Amides XIV were added to a prepared solution of an appropriatealcohol, triphenylphosphine, and diethyl azodicarboxylate to givecompounds of Formula I wherein X is OR₅ and R₁ is hydrogen.

Process 9

(i) Amides I, wherein Z is Br or I and produced by Process IV, werecoupled with phenylacetylene under the aegis oftetrakis(triphenylphosphine) palladium(0) to give compounds of Formula Iwherein Z is phenylacetylene.

(ii) Amides I, produced above, were hydrogenated over palladium oncarbon catalyst to produce compounds of Formula I wherein Z ishydrocinnamyl.

Process 10

(i) Amides I, wherein Z is I and produced by Process IV, were heated atreflux in pyridine in the presence of cuprous cyanide to producecompounds of Formula I wherein Z is cyano.

Process 11

(i) Amides I, wherein Z is I and produced by Process IV, were subjectedto Mitsonobu coupling in the presence of aqueous barium hydroxide,phenylboric acid, tetrakis(triphenylphosphine) palladium(0) anddimethoxyethane to produce Formula I compounds wherein Z is phenyl.

Process 12 (Reactions a-h)

(i) Reduction via sodium borohydride of 3-methoxy cinnamic acid (XV),followed by sequential treatment with iodine and hydrochloric acidproduced allylic alcohol XVI.

(ii) Compound XVI was acylated via acetic anhydride in pyridine toproduce allylic acetate XVII.

(iii) Allylic acetate XVII was cyclopropanated via treatment with sodiumchlorodifluoroacetate in refluxing diglyme to produce thedifluorocyclopropane XVIII.

(iv) Difluorocyclopropane XVIII was treated with potassium hydroxide inmethanol to give the corresponding alcohol XIX.

(v) Alcohol XIX was converted to a mesylate via treatment withmethanesulfonyl chloride in dichloromethane in the presence oftriethylamine. The mesylate was digested with dimethylformamide andtreated with sodium azide to give the corresponding azide. The azide wasreduced via lithium aluminum hydride to the amine XX.

(vi) Amine XX was converted to Amides I, wherein R is fluorine, byacylation with an acyl chloride in the presence of triethylamine.

Process 13 (Reactions a,b)

(i) Oxime XXI, produced as in Process II, was converted to diamine XXIIvia catalytic hydrogenation over palladium on carbon in acetic acid.

(ii) Diamine XXII was diacylated via treatment with two equivalents ofan acyl chloride in the presence of triethylamine to give Amides I,wherein Z is alkamido.

Process 14 (Reactions a-d)

(i) Alcohol IX, produced via Process III, was oxidized via Swernoxidation to give the corresponding carboxaldehyde, which was treatedwith methyl magnesium bromide to give a mixture of diastereomers. Theepimers were separated by chromatography to produce pure alcohols XXIII.

(ii) Alcohol XXIII was converted by treatment with phthalimide,diethylazo dicarboxylate, and triphenylphosphine to the phthalimideXXIV.

(iii) Phthalimide XXIV was treated with hydrazine in ethanol to giveamine XXV.

(iv) Acylation of XXV was accomplished with an acyl chloride in thepresence of triethylamine to give compounds of Formula I, wherein G isalkmethylene.

Process 15

(i) Phenol XIV, produced via Process VII, was converted to the sodiumsalt by treatment with sodium hydroxide and heated at reflux withethylene carbonate in toluene to give Amides I, wherein R₅ is2-hydroxyethyl.

Process 16 (Reactions a-c)

(i) Alcohol IX, produced via Process III, was treated withmethanesulfonyl chloride in the presence of triethylamine to give amesylate which was subsequently transformed, via treatment with sodiumcyanide in dimethylformamide, to nitrile XXVI.

(ii) Nitrile XXVI was reduced with lithium aluminum hydride intetrahydrofuran to give amine XXVII.

(iii) Amine XXVII was acylated with an acid chloride in the presence oftriethylamine to give Amides I, wherein G is ethylene.

Process 17 (Reactions a-e)

(i) Commercially available 3-methoxycinnamic acid ethyl ester wascyclopropanated with the ylide derived from isopropyltriphenylphosphonium iodide and butyllithium to give cyclopropane XXVI.

(ii) Cyclopropane XXVI was converted to alcohol XXIX via reduction withlithium aluminum hydride in tetrahydrofuran.

(iii) Alcohol XXIX was treated with methanesulfonyl chloride andtriethylamine in dichloromethane to produce a mesylate which wassubsequently converted to azide XXX by treatment with sodium azide indimethylformamide.

(iv) Azide XXX was reduced via lithium aluminum hydride intetrahydrofuran to amine XXXI.

(v) Amine XXXI was acylated with an acyl halide and triethylamine togive Amides I, wherein R is methyl.

Reagents, solvents and reaction conditions for the above describedpreparative steps would be known to one skilled in the art of organicsynthesis. All steps are conventional organic reactions having extensiveprecedent in the scientific literature.

These preparative methods may be varied in order to produce othercompounds embraced by this invention but not specifically disclosed.

Additionally compounds of Formula I also encompass all pharmaceuticallyacceptable solvates, with hydrates being the preferred solvates. Thepresent invention also includes geometrical isomers as well as opticalisomers, e.g. mixtures of enantiomers as well as individual enantiomersand diastereomers, which arise as a consequence of structural asymmetryin certain compounds of the instant series. Trans-cyclopropanestereoisomers are in general preferred. Separation or stereospecificsynthesis of the individual isomers is accomplished by application ofvarious methods which are well known to practitioners in the art.

In addition, the invention includes isotopically labeled variants of thedisclosed compounds, particularly radioiodinated compounds into which aradioactive isotope of iodine, such as ¹²² I, ¹²³ I, ¹²⁵ I, or ¹³¹ I,has been incorporated; such radiolabeled compounds are of utility asspecific, high affinity receptors and thus can be employed in receptorbinding assays, autoradiographic studies, and in other in vitro and invivo biological tests which are used in the discovery andpharmacological characterization of novel melatonergic agents.

The "Description of Specific Embodiments" section hereinbelow providesgreater descriptive details of the synthesis of compounds of Formula Iand of intermediates of Formulas II-XXXI.

The compounds of the present invention have affinity for receptors ofthe endogenous pineal hormone, melatonin, as determined in a receptorbinding assay, and exhibit agonist activity as determined by afunctional assay. The biological tests are described below.

As is discussed above, melatonin is involved in the regulation of avariety of biological rhythms and exerts its biological effects viainteraction with specific receptors. There is evidence that theadministration of melatonin agonists is of clinical utility in thetreatment of various conditions regulated by melatonin activity. Suchconditions include depression, jet-lag, work-shift syndrome, sleepdisorders, glaucoma, some disorders associated with reproduction,cancer, immune disorders and neuroendocrine disorders.

The systemic administration and dosing regimen of compounds of Formula Ican be done in a manner similar to that described for melatonin itself.The dosage and dosage regimen must be adjusted using sound professionaljudgment and taking into consideration such variables as the age, bodyweight, sex and physical condition of the recipient, the route ofadministration and the nature of the illness being treated. Oral,transdermal, subcutaneous, intravenous, intramuscular, rectal, buccal,intranasal, and ocular routes of administration may be used.

One or more of the compounds of the invention is mixed withpharmaceutically acceptable amounts of one or more conventionalpharmaceutical excipients to produce a formulation to be administered bythe desired route. Generally, such formulations will contain one orseveral carriers or diluents. Useful carriers include solids,semi-solids and liquids which have miscibility, or other comparability,with the active agent(s) so that they can deliver same to a patient orhost.

Suitable carriers include lactose, dextrose, sucrose, sorbitol,mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl-and propyl-hydroxybenzoates, talc, magnesium stearate, mineral oil andthe like. Mixures are operable.

Other useful excipients include lubricants, wetting agents, gellants,emulsifiers, preservatives, colorants, perfumes, flavor enhancers,drying agents and the like. Mixtures can be employed.

Generally, compositions which include the compounds of the inventionwill contain from about 0.10 to about 10% of active compound(s) and99.90 to 90%, or other suitable amounts, of excipient(s).

Dosage levels will be dictated by the patient's needs and by the medicaljudgment of the treating physician. Generally, however, dosages of about0.1 mg to about 100 mg per day are useful to treat sleep, circadianrhythm or other medical disorders.

In methods of treatment employing the compounds of the invention, thetreatment will involve the step(s) of administering one or more dosagesof the compound to a host, preferably a mammalian, e.g. human host inneed of such treatment.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The compounds which constitute the present invention, their methods ofpreparation and their biological actions will appear more fully afterconsideration of the following examples, which are given for the purposeof illustration only and are not to be construed as limiting theinvention's scope.

In the following examples, temperatures are expressed in degrees Celsius(°C.), hours are designated "h" or "hr", and melting points areuncorrected. The proton nuclear magnetic resonance (NMR) spectralcharacteristics refer to chemical shifts (δ) expressed as parts permillion (ppm) versus tetramethylsilane (TMS) as the reference standard.The relative area reported for NMR signals at various chemical shiftscorresponds to the number of hydrogen atoms of a particular type in themolecule. The multiplicities of the signals are reported as broadsinglet (br s), singlet (s), doublet (d), triplet (t) or multiplet (m).The NMR spectra were obtained using solutions of the compounds in eitherdeuterodimethylsulfoxide (DMSO-d₆) or deuterochioroform (CDCl₃).Infrared (IR) spectral descriptions include only absorption wave numbers(cm-1) having functional group identification value and IRdeterminations were made using potassium bromide (KBr) as diluent. Theelemental analyses are reported as percent by weight.

The following examples describe in detail the preparation ofrepresentative examples of compounds of Formula I and of syntheticintermediates. It will be apparent to those skilled in the art thatmodifications, both of material and methods, will allow preparation ofother compounds disclosed herein. From the foregoing description and thefollowing examples it is believed that one skilled in the art would beable to carry out the invention to the fullest extent.

EXAMPLES Example 1 (Process 1)

Preparation of(tran5)-N-rf2-(2-Fluoro-5-methoxyphenyl)cyclopropyl!methyl!-2-methylpropanamide

Step i

(a) (trans)-3-(2-Fluoro-5-methoxyphenyl)-2-propenenitrile: To asuspension of NaH (6.90 g, 60% dispersion in mineral oil, 173 mmol) inTHF (500 mL) at 0° C. was added diethyl cyanomethylphosphonate (30.10 g,170 mmol) dropwise. This was followed by the dropwise addition of asolution of 2-fluoro-5-methoxybenzaldehyde (24.5 g, 159 mmol) in THF (50mL). The resulting suspension was allowed to warm to ambienttemperature. After 18 h, H₂ O (200 mL) was added and the solution wasextracted with EtOAc. The organics were combined, washed with brine,dried over MgSO₄, and concentrated to afford a white waxy solid. Thematerial was then purified by Kugelrohr distillation to give the titlecompound, 24.3 g (86%): mp 56°-57° C.; ¹ H NMR (300 MHz, CDCl₃) 8 3.79(s, 3H), 5.98 (d, J=16.1 Hz, 1H), 6.85-6.90 (m, 1H), 6.91-6.93 (m, 1H),6.99 (t, j=6.5 Hz, 1H), 7.43 (d, J=16.1 Hz, 1H); (isobutane-DCI) m/e177; Analysis calc'd for C₁₀ H₈ NOF: C, 67.79; H, 4.55; N, 7.91; found:C, 67.41; H, 4.44; N, 7.86.

(b) (trans)-2-(2-Fluoro-5-methoxyphenyl)cyclopropane carbonitrile: To asuspension of NaH (1.73 g, 72 mmol) in DMSO (40 mL) was added solidtrimethylsulfoxonium iodide (15.9 g, 72 mmol) in small portions. Afterthe foaming had subsided (40 min), a solution of(trans)-3-(2-fluoro-5-methoxyphenyl)-2-propenenitrile (4.26 g, 24 mmol)in DMSO (10 mL) was added dropwise, maintaining the temperature between35°-40 C. Stirring was continued for 18 h at room temperature, followedby the dropwise addition of saturated NH₄ Cl (100 mL) and extractionwith ethyl acetate. The organics were combined, washed with brine, dried(K₂ CO₃), and concentrated to give a red oil which was then purified bysilica gel chromatography (CH₂ Cl₂ /hexane, 60:40) to afford the titlecompound as a clear oil (46% yield): ¹ H NMR (300 MHz, CDCl₃) δ0.82-0.88 (m, 2H), 1.65-1.75 (m, 1H), 2.55-2.62 (m, 1H), 3.75 (s, 3H),6.50-6.55 (m, 1H), 6.60-6.7 (m, 1H), 6.92 (t, J=6.5 Hz, 1H).

Step ii

(c) (trans)-2-(2-Fluoro-5-methoxyphenyl)cyclopropanemethanamine: Asuspension of (trans)-2-(2-fluoro-5-methoxyphenyl)cyclopropanecarbonitrile (5.0 g, 26 mmol), PtO₂ (200 mg), and CHCl₃ (10 mL) in EtOH(65 mL) was hydrogenated in a Parr apparatus at 55 psi for 3 h. Thecatalyst was filtered through a plug of celite and the solvents wereremoved. The resulting hydrochloride salt was then partitioned betweenCH₂ Cl₂ and 10% K₂ CO₃. The organic layer was separated, dried over K₂CO₃, and concentrated to afford the title compound as the free amine,3.8 g (74%): ¹ H NMR (250 MHz, CDCl₃) δ 0.79-0.82 (m, 1H), 0.90-0.95 (m,1H), 1.49 (br s, 2H), 1.70-1.76 (m, 1H), 1.82-1.86 (m, 1H), 2.60-2.74(m, 2H), 3.75 (s, 3H), 6.3-6.42 (m, 1H), 6.50-6.62 (m, 1H), 6.85-6.90(m, 1H).

(d) (trans)-N-2-(2-Fluoro-5methoxyphenyl)cyclopropyl!methyl!-2-methylpropanamide:

To a magnetically stirred solution of(trans)-2-(2-fluoro-5-methoxyphenyl)cyclopropanemethanamine (600 mg, 3.1mmol), Et₃ N (909 mg, 9.0 mmol), in dry dichloromethane (15 mL) at 0° C.was added isobutyryl chloride (352 mg, 3.3 mmol) dropwise. The resultingsuspension was then allowed to warm to room temperature and stirred for18 h. The solvents were removed and the residue was taken into EtOAc(100 mL) and washed sequentially with H₂ O, 5% citric acid, 5% K₂ CO₃,brine, and dried over K₂ CO₃. Concentration by rotary evaporationyielded a crude oil which was then purified by Kugelrohr distillation.Recrystallization of the resultant solid from Et₂ O/hexane (1:1) gave380 mg (47% yield) of the title compound: mp 93°-94° C.; ¹ H NMR (300MHz, CDCl₃) δ 0.82-0.88 (m, 1H), 0.97-1.03 (m, 1H), 1.13 (d, J=8.1 Hz,6H), 1.14-1.24 (m, 1H), 1.85-1.91 (m, 1H), 2.25-2.30 (m, 1H), 2.93-3.02(m, 1H), 3.52 (dt, J=7.8, 13.8 Hz, 1H), 3.72 (s, 3H), 5.74 (br s, 1H),6.41-6.44 (m, 1H), 6.59-6.64 (m, 1H), 6.91 (t, J=6.5 Hz, 1H); IR (NaClFilm) 3298, 2962, 1642, 1546, 1502, 1428 cm⁻¹ ; MS (isobutane-DCI) m/e253; Analysis calc'd for C₁₅ H₂₀ NO₂ F: C, 67.90; H, 7.60; N, 5.28;found: C, 68.18; H, 7.77; N, 5.24.

Example 2 (Process 2)

Preparation of (trans)-N-2-(3-Methoxyphenyl)cyclopropyl!methyl!butanamide

Step i

(a)(b) (trans)-N-Methoxy-N-methyl-3-(3-methoxyphenyl)-2-propenamide: Asolution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionylchloride (250 mL) was heated at reflux for 1 h. The majority of the thethionyl chloride was then distilled off and the resulting residue wastreated with dichloromethane and residual thionyl chloride was removedby codistillation to give 3-methoxycinnamic acid chloride of sufficientpurity to be used without further purification. Pyridine (186 mL, 2.3mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol)were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42mol) in dry dichloromethane (500 mL). The solution was stirred for 18 hat room temperature, diluted with dichloromethane (200 mL), and washedsequentially with 1N HCl, saturated sodium bicarbonate, and brine. Itwas then dried over MgSO₄ and concentrated in vacuo to give the titlecompound as a dark oil (88.43 g, 95%): ¹ H NMR (300 MHz, CDCl₃) δ 3.25(s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H),7.72 (d, J=16.0 Hz, 1H).

(c) (trans)-N-Methoxy-N-methyl-2-(3-methoxyphenyl)cyclopropanecarboxamide: To a suspension of NaH (16.27 g, 0.68 mol) inDMSO (375 mL) was added solid trimethylsulfoxonium iodide (149.16 g,0.68 mol) in small portions. After the foaming had subsided (40 min), asolution of (trans)-N-methoxy-N-methyl-3-(3-methoxyphenyl)-2-propenamide(50 g, 0.23 mol) in DMSO (50 mL) was added dropwise, maintaining thetemperature between 35°-40° C. Stirring was continued for 18 h at roomtemperature, followed by the dropwise addition of saturated NH₄ Cl (400mL) and extraction with ethyl acetate. The organics were combined,washed with brine, dried (K₂ CO₃), and concentrated to give a red oilwhich was then purified by Kugelrohr distillation (130° C., 0.5 mm Hg)to afford the title compound as a white wax (52.47 g, 100%): ¹ H NMR(300 MHz, CDCl₃) δ 0.82-0.88 (m, 1H), 1.20-1.30 (m, 1H), 1.59-1.62 (m,1H), 2.40-2.45 (m, 1H), 3.22 (s, 3H), 3.68 (s, 3H), 3.79 (s, 3H),6.61-6.72 (m, 3H), 7.18 (t, J=6.0 Hz, 1H).

Step ii

(d) (trans)-2-(3-Methoxyphenyl)cyclopropanecarboxaldehyde: To a rapidlystirred suspension of LiAlH₄ (7.74 g, 204 mmol) in THF (800 mL) at -45°C. was added a solution of the(trans)-N-methoxy-N-methyl-2-(3-methoxyphenyl)cyclopropanecarboxamide(40 g, 171 mmol) in THF (100 mL) maintaining the temperature below -40°C. by dropwise addition. After addition the cooling bath was removed andthe reaction was allowed to warm to 5° C., then immediately recooled to-45° C. Potassium hydrogen sulfate (40 g, 300 mmol) in H₂ O(120 mL) wascautiously added dropwise, the temperature maintained below -30° C.throughout. After addition the cooling bath was removed and thesuspension was stirred at room temperature for 30 min. The mixture wasfiltered through celite and the filter cake was washed with ether. Thecombined filtrates were then washed with cold 1N HCl, 5% K₂ CO₃, brine,and dried over MgSO₄. Concentration by rotary evaporation yielded thetitle compound as a clear oil (29.9 g, 99%): ¹ H NMR (300 MHz, CDCl₃) δ1.49-1.58 (m, 1H), 1.65-1.73 (m, 1H), 2.10-2.19(m, 1H), 2.58-2.67 (m,1H), 3.80 (s, 3H), 6.66-6.78 (m, 3H), 7.21 (t, J=6.6 Hz, 1H), 9.32 (d,J=2.0 Hz, 1H).

Step iii

(e)(f) (trans)- 2-(3-Methoxyphenyl)cyclopropanemethanamine: A solutionof (trans)-2-(3-methoxyphenyl)cyclopropanecarboxaldehyde (31.0 g, 176mmol), hydroxylamine hydrochloride (38.57 g, 555 mmol), ethanol (200mL), water (120 mL), and 10N NaOH (55 mL, 555 mmol) was heated at reflux(steam bath) for 18 h. The solution was cooled to room temperature,diluted with water (1 L), washed sequentially with 1N HCl, H₂ O, brine,and dried over K₂ CO₃. Concentration by rotary evaporation produced30.98 g (92%) of the oxime which was used directly in the next step. Theoxime (30.98 g, 162 mmol) was digested with THF (50 mL) and addeddropwise to a -45° C. suspension of LiAlH₄ (9.2 g, 242 mmol), in THF(300 mL) maintaining the temperature below -40° C. The reaction was thenallowed to come to ambient temperature, stirred for 4 h, and recooled to-45° C. Potassium hydrogen sulfate (55 g, 404 mmol) in H₂ O(200 mL) wasthen cautiously added dropwise. The cooling bath was removed and thesuspension was stirred at room temperature for 30 min. The resultingpaste was then filtered through celite, and the filter cake was washedwith Et₂ O. The combined filtrates were extracted with 1N HCl, the acidextracts were made basic (50% NaOH), and then extracted withdichloromethane. The organics were combined, washed with brine, dried(K₂ CO₃), and concentrated in vacuo to give the title compound as aclear oil (17.62 g, 56%, two steps): ¹ H NMR (300 MHz, CDCl₃) δ0.80-0.95 (m, 2H), 1.31-1.35 (m, 1H), 1.70-1.79 (m, 1H), 2.28 (br s,2H), 2.70-2.74 (m, 2H), 3.79 (s, 3H), 6.60-6.71 (m, 3H), 7.17 (t, J=6.4Hz, 1H).

Step iv

(g) (trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!butanamide: To amagnetically stirred solution of (trans)-2-(3-methoxyphenyl)-cyclopropanemethanamine (1.02 g, 5.8 mmol) and Et₃ N(1.60 mL, 11.5 mmol) in dry dichloromethane (20 mL) at 0° C. was addedbutyryl chloride (0.69 g, 6.4 mmol) dropwise. The resulting suspensionwas allowed to warm to room temperature and stirred for 4 h. Thesolvents were removed and the residue was digested with EtOAc (100 mL)and washed sequentially with H₂ O, 5% citric acid, 5% K₂ CO₃, brine, anddried over K₂ CO₃. Concentration by rotary evaporation yielded a crudeproduct which was then purified by flash chromatography (silica gel, 40%EtOAc/hexane) to afford 1.01 g (71%) of the title compound: ¹ H NMR (300MHz, CDCl₃) δ 0.85-0.95 (m, 5H), 1.22-1.31 (m, 1H), 1.62 (q, J=7.1 Hz,2H), 1.73-1.77 (m, 1H), 2.13 (t, J=7.7 Hz, 2H), 3.15-3.36 (m, 2H), 3.76(s, 3H), 5.59 (s, 1H), 6.55-6.69 (m, 3H), 7.15 (t, J=6.5 Hz, 1H); IR(NaCl Film) 3302, 2862, 1732, 1644, 1464 cm⁻¹ ; MS (isobutane-DCI) m/e247; Analysis calc'd for C₁₅ H₂₁ NO₂ : C, 72.84; H, 8.56; N, 5.66;found: C, 72.71; H, 8.50; N, 5.62.

Example 3 (Process 3)

3a. Preparation of (+)-(trans)-N-2-(3-Methoxyphenyl)cyclopropyl!methyl!-butanamide

Step i

(a) (+)-(trans)-2-(3-Methoxyphenyl)cyclopropanemethanol: To a suspensionof LAH (0.65 g, 17.1 mmol) in THF (45 mL) at -45° C. was added asolution of (2'S)-N-(1S,2S)-2-(3-methoxyphenyl)cyclopropanecarbonyl!bornane-10', 2'-sultam (3.36g, 8.6 mmol), prepared according to the method of Vallgarda, J.;Appelberg, U.; Csoregh, I.; and Hacksell, U. (J. Chem. Soc. PerkinTrans. I, pages 461-470, 1994), in THF (20 mL) dropwise. The coolingbath was then removed and the reaction was allowed to warm to roomtemperature, followed by immediate recooling to -45° C. Potassiumhydrogen sulfate (3.9 g, 29 mmol) in H₂ O (15 mL) was cautiously added,allowing the temperature to rise to -5° C. The resulting paste wasstirred at room temperature for 1 h, filtered through celite, and thefilter cake was washed with Et₂ O. The combined filtrates were washedwith cold (0° C.) 1N HCl, 5% K₂ CO₃, brine, dried (K₂ CO₃), andconcentrated to give a crude wax. Trituration with hexane, filtration ofthe precipitated chiral auxiliary, and subsequent concentration of thefiltrate afforded the title compound as a clear oil (1.33 g, 87%): ¹ HNMR (300 MHz, CDCl₃) δ 0.90-1.00 (m, 2H), 1.21-1.25 (m, 1H), 1.52-1.59(br s, 1H), 1.78-1.85 (m, 1H), 3.60 (dd, J=5.0, <1 Hz, 2H), 3.80 (s,3H), 6.60-6.72 (m, 3H), 7.20 (t, J=7.5 Hz, 1H); a!_(D) ²⁰ 55.5° C. (c=1,CH₂ Cl₂).

Step ii

(b)(c) (+)-(trans)-1-(Azidomethyl)-2-(3-methoxyphenyl)cyclopropane: To asolution of (+)-(trans)-2-(3-methoxyphenyl)cyclopropanemethanol (1.33 g,7.5 mmol) and triethylamine (1.57 mL, 11.3 mmol) in dichloromethane (25mL) at 0° C. was added methanesulfonyl chloride (950 mg, 8.3 mmol)dropwise. After addition was complete the ice bath was removed andstirring was continued for 30 min. The solution was treated withdichloromethane (100 mL), washed with H₂ O, saturated NaHCO₃, and driedover K₂ CO₃. Concentration by rotary evaporation gave 1.78 g of a crudeoil. The mesylate was taken into DMF (25 mL), treated with sodium azide(980 mg, 15 mmol) and allowed to stir at room temperature for 18 h. Themixture was concentrated and the residue was taken into Et₂ O, washedwith H₂ O, brine, and the solvents removed by rotary evaporation toproduce 1.11 g (73%, two steps) of a clear oil: ¹ H NMR (300 MHz, CDCl₃)δ 0.85-0.92 (m, 2H), 1.41-1.45 (m, 1H), 1.80-1.83 (m, 1H), 3.25-3.38 (m,1H), 3.48-3.58 (m, 1H), 3.83 (s, 3H), 6.70-6.78 (m, 3H), 7.21 (t, J=7.8Hz, 1H).

(d) (+)-(trans)-2-(3-Methoxyphenyl)cyclopropanemethanamine: To a stirredsuspension of LAlH₄ (455 mg, 12 mmol) in THF (20 mL) at -30° C. wasadded a solution of(+)-(trans)-1-(azidomethyl)-2-(3-methoxyphenyl)cyclopropane (1.11 g, 5.5mmol) in THF (10 mL). The temperature was maintained below -30° C.,throughout. After addition was complete the suspension was allowed towarm to room temperature and stirred for 4 h. The reaction was cooled to-45° C. and a solution of KHSO₄ (2.6 g) in H₂ O(20 mL) was cautiouslyadded dropwise. The suspension was stirred at room temperature for 30min, filtered through celite, and the filter cake was washed well withEt₂ O. The filtrates were combined, extracted with 1N HCl and the acidiclayers were basified (30% NaOH). The basic solution was extracted withCH₂ Cl₂, dried (K₂ CO₃), and concentrated to afford 400 mg (41%) of thetitle compound as a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ 0.86-0.95 (m,2H), 1.24-1.31 (m, 1H), 1.72-1.79 (m, 1H), 2.1-2.40 (br s, 2H),2.70-2.74 (m, 2H), 3.79 (s, 3H), 6.60-6.72 (m, 3H), 7.15 (t, J=7.8 Hz,1H).

Step iii

(e) (+)-(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!butanamide: Toa magnetically stirred solution of(+)-(trans)-2-(3-methoxyphenyl)cyclopropanemethanamine (400 mg, 2.3mmol) and Et₃ N (1.1 mL, 7.9 mmol) in dry dichloromethane (15 mL) at 0°C. was added butyryl chloride (269 mg, 2.5 mmol) dropwise. The resultingsuspension was allowed to come to room temperature and stirred for 18 h.The solvents were removed and the residue was digested with EtOAc (100mL) and washed sequentially with H₂ O, 5% citric acid, 5% K₂ CO₃, brine,and dried over K₂ CO₃. Concentration by rotary evaporation yielded acrude product which was then purified by flash chromatography (silicagel, 1% MeOH/CH₂ Cl₂) to afford 310 mg (56% ) of the title compound as aclear oil: ¹ H NMR (300 MHz, CDCl₃) 5 0.86-0.95 (m, 5H), 1.22-1.31 (m,1H), 1.54-1.83 (m, 3H), 2.08 (t, J=7.7 Hz, 2H), 3.16-3.36 (m, 2H), 3.76(s, 3H), 5.59 (br s, 1H), 6.55-6.76 (m, 3H), 7.17 (t, J=7.8 Hz, 1H); IR(NaCl Film) 3296, 2962, 1644, 1604, 1550, 1494 cm⁻¹ ; MS (isobutane-DCI)m/e 247; a!_(D) ²⁰ +57.2° (c=1, CH₂ Cl₂); Analysis calc'd for C₁₅ H₂₁NO₂ 0.15 H₂ O: C, 72.05; H, 8.59; N, 5.60; found: C, 71.97; H, 8.59; N,5.60.

3b. (-)-(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!methyl!butanamide: Thetitle compound was synthesized by the above method from(2'R)-N-(1R,2R)-2-(3-methoxyphenyl)cyclopropanecarbonyl!bornane-10',2'-sultam, prepared according to the method of Vallgorda, J.; Appelberg,U.; Csoregh, I.; and Hacksell, U. (J. Chem. Soc. Perkin Trans. I, pages461-470, 1994): ¹ H NMR (300 MHz, CDCl₃) δ 0.86-0.95 (m, 5H), 1.22-1.31(m, 1H), 1.54-1.83, (m, 3H), 2.08 (q, J=7.7 Hz, 2H), 3.16-3.36 (m, 2H),3.76 (s, 3H), 5.59 (br s, 1H), 6.55-6.76 (m, 3H), 7.17 (t, J=7.8 Hz,1H); IR (NaCl Film) 3294, 2962, 1644, 1604, 1550, 1494 cm⁻¹ ; MS(isobutane-DCI) m/e 247.

Example 4 (Process 4)

4a. Preparation of (trans)-N-2-(2-Iodo-5-methoxyphenyl)cyclopropyl!methyl!butanamide

To a stirred solution of (trans)-N- 2-(3-methoxyphenyl)cyclopropyl!methyl!butanamide (120 mg, 0.49 mmol) and Tl(OAc)₃ (522 mg,1.5 mmol) in CCl₄ (10 mL) was added a solution of I₂ (139 mg, 0.55 mmol)in CCl₄ (20 mL). The resulting suspension was heated at reflux for 18 h.The suspension was cooled to ambient temperature, filtered through amedium pore glass frit, and the filtrate washed with saturated sodiumthiosulfate, brine, and dried (K₂ CO₃). Concentration by rotaryevaporation gave 150 mg of an orange oil which was purified bychromatography (silica gel, 40% EtOAc/hexane) to afford 108 mg (60%) ofthe title compound as a white solid: mp 84°-86° C.; ¹ H NMR (300 MHz,CDCl₃) δ 0.87-1.01 (m, 5H), 1.07-1.23 (m, 1H), 1.59-1.71 (m, 2H),1.84-1.90 (m, 1H), 2.16 (t, J=7.8 Hz, 2H), 3.16-3.25 (m, 1H), 3.46-3.53(m, 1H), 3.73 (s, 3H), 5.83 (br s, 1H), 6.45-6.50 (m, 2H), 7.66 (d,J=8.5 Hz, 1H); IR (NaCl Film) 3304, 2962, 1636, 1556, 1444, 1416 cm⁻¹ ;MS (isobutane-DCI) m/e 373; Analysis calc'd for C₁₅ H₂₀ NO₂ I: C, 48.27;H, 5.40; N, 3.75; found: C, 48.24; H, 5.41; N, 3.53.

4b. Preparation of (trans)-N-2-(2-Iodo-5-fluorophenyl)cyclopropyl!methyl!butanamide

To a stirred solution of (trans)-N- 2-(3-fluorophenyl)cyclopropyl!methyl!butanamide (1.0 g, 4.3 mmol), Tl(OAc)₃ (2.5 g, 6.5mmol), and TFA (15 mL) in acetonitrile (15 mL) was added a solution ofNaI (705 mg, 4.7 mmol) in H₂ O(2 mL). The resulting suspension washeated at 55° C. for 12 h. The suspension was cooled to ambienttemperature, filtered through a medium pore glass frit, and the filtratewashed with saturated sodium thiosulfate, brine, and dried (K₂ CO₃).Concentration by rotary evaporation gave 1.26 g of an orange oil whichwas purified by chromatography (silica gel, 35% EtOAc/hexane) to afford371 mg (25%) of the title compound as a white solid: mp 66-68° C.; ¹ HNMR (300 MHz, CDCl₃) δ 0.91-0.99 (m, 5H), 1.00-1.15 (m, 1H), 1.70 (q,J=7.5 Hz, 2H), 1.89-1.92 (m, 1H), 2.17 (t, J=7.2 Hz, 2H), 3.28-3.32 (m,1H), 3.43-3.50 (m, 1H), 5.67 (br s, 1H), 6.59-6.67 (m, 2H), 7.71-7.76(m, 1H); IR (NaCl Film) 3417, 3294, 2962, 1638, 1554, 1448, 1412 cm⁻¹ ;MS (ESI) m/e 361; Analysis calc'd for C₁₄ H₁₇ NOFI: C, 46.55; H, 4.74,N, 3.88; found: C, 46.57; H, 4.68; N, 3.85.

Example 5 (Process 5)

Preparation of (trans)-N- 2-(2,4-Dibromo-5-methoxyphenyl)cyclopropyl!methyl!butanamide

To a stirred solution of N-2-(3-methoxyphenyl)cyclopropyl!methyl!butanamide (190 mg, 0.77 mmol),and Tl(OAc)₃ (881 mg, 2.3 mmol) in CCl₄ (20 mL) at 0° C. was added asolution of Br₂ (238 mg, 1.5 mmol) in CCl₄ (10 mL) dropwise. Afteraddition was complete the suspension was filtered through a medium poreglass frit and the filtrate washed with saturated sodium thiosulfate,brine, dried (K₂ CO₃) and concentrated to give a clear oil. Purificationby chromatography (silica gel, 35% EtOAc/hexane) afforded 185 mg (62%)of the title compound as a white solid: m.p. 114°-115° C.; ¹ H NMR (300MHz, CDCl₃) δ 0.90-1.02 (m, 5H), 1.04-1.16 (m, 1H), 1.60-1.69 (m, 2H),1.89-1.93 (m, 1H), 2.16 (t, J=7.8 Hz, 2H), 3.04-3.16 (m, 1H), 3.49-3.54(m, 1H), 3.82 (s, 3H), 5.77 (br s, 1H), 6.44 (s, 1H), 7.66 (s, 1H); IR(NaCl Film) 3290, 2960, 1632, 1550, 1474, 1442 cm⁻¹ ; MS m/e 405;Analysis calc'd for C₁₅ H₁₉ NO₂ Br₂ : C, 44.47; H, 4.73; N, 3.46; found:C, 44.59; H, 4.65; N, 3.16.

Example 6 (Process 6)

Preparation of (trans)-N-2-(3-Methoxyphenyl)cyclopropyl!methyl!-N-(phenylmethyl) butanamide

A magnetically stirred solution of (trans)-N- 2-(3-methoxyphenyl)cyclopropyl!methyl!butanamide (1.0 g, 4.0 mmol) and NaH(105 mg, 4.4 mmol) in DMF (10 mL) was treated with benzyl bromide (750mg, 4.4 mmol). The suspension was stirred for 18 h at room temperature,diluted with Et₂ O (100 mL), and quenched with H₂ O(100 mL). The layerswere separated and the organic phase was washed with H₂ O, brine, dried(K₂ CO₃) and concentrated to give a crude oil which was purified byflash chromatography (silica gel, 45% EtOAc/Hexane) to afford 580 mg(43%) of the title compound as a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ0.78-0.98 (m, 4H), 1.17-1.33 (m, 1H), 1.60-1.79 (m, 4H), 2.27-2.44 (m,2H), 3.17-3.33 (m, 1H), 3.51-3.61 (m, 1H), 3.77 (br s, 3H), 4.46-4.82(m, 2H), 6.50-6.72 (m, 3H), 7.10-7.34 (m, 6H); IR (NaCl Film) 2962,1644, 1604, 1454, 1210 cm⁻¹ ; MS (isobutane-DCI) mle 337; Analysiscalc'd for C₂₂ H₂₇ NO₂ 0.1 H₂ O: C, 77.88; H, 8.08; N, 4.13; found: C,77.87; H, 8.12; N, 3.89.

Example 7 (Process 7)

Preparation of (trans)-N- 2-3-(2-Propenyloxy)phenyl!cyclopropyl!methyl!butanamide

Step i

(a). (trans)-N- 2-(3-Hydroxyphenyl)cyclopropyl!methyl!butanamide: To astirred solution of (trans)-N-2-(3-methoxyphenyl)cyclopropyl!methyl!butanamide (3.50 g, 14.2 mmol) indichloromethane (50 mL) at -78° C. was added BBr₃ (28.4 mL, 1N in CH₂Cl₂, 28.4 mmol) dropwise. After addition was complete, the cooling bathwas removed and stirring was continued for 18 h. The solution was pouredover ice/H₂ O(100 mL) and extracted with 2.5 N NaOH. The basic extractswere combined, washed with dichloromethane, and acidified (conc. HCl).The acidic solution was extracted with dichloromethane, the organicswere combined, washed with brine, dried (MgSO₄), and concentrated toafford 2.49 g (75%) of the title compound: ¹ H NMR (300 MHz, DMSO-d₆) δ0.72-0.84 (m, 5H), 1.09-1.15 (m, 1H), 1.42-1.54 (m, 2H), 1.63-1.69 (m,1H), 2.02 (t, J=5.0 Hz, 2H), 2.99-3.11 (m, 2H), 6.39-6.50 (m, 3H), 6.98(t, J=7.8 Hz, 1H), 7.91 (s, 1H), 9.19 (br s, 1H); IR (NaCl Film) 3300,2964, 1642, 1585, 1542, 1466 cm⁻¹ ; MS (isobutane-DCI) m/e 233; Analysiscalc'd for C₁₄ H₁₉ NO₂.0.1 H₂ O: C, 71.52; H, 8.23; N, 5.96; found: C,71.53; H, 8.32; N, 5.92.

Step ii

(b). (trans)-N- (2-Propen-1-yloxyphenyl)cyclopropyl!methyl!butanamide:To a rapidly stirred solution of (trans)-N- 2-(3hydroxyphenyl)cyclopropyl!methyl!butanamide (0.8 g, 3.4 mmol) and KOH(210 mg, 3.74 mmol) in ethanol (15 mL) was added allyl iodide (622 mg,3.7 mmol). After stirring for 18 h, the suspension was diluted with Et₂O (100 mL), and washed with H₂ O, 2N NaOH, brine, dried (K₂ CO₃), andconcentrated to a give a crude residue. The resulting material waspurified by chromatography (silica gel, 40% EtOAc/hexane) to afford 320mg (34%) of the title compound: ¹ H NMR (300 MHz, CDCl₃) δ 0.70-0.94 (m,5H), 1.12-1.32 (m, 1H), 1.58-1.84 (m, 3H), 2.20 (t, J=6.0 Hz, 2H),3.15-3.36 (m, 2H), 4.48 (d, J=5.6 Hz, 2H), 5.24 (d, J=10.0 Hz, 1H), 5.40(d, J=17.2 Hz, 1H), 5.56 (br s, 1H), 5.96-6.07 (m, 1H), 6.57-6.70 (m,3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3296, 2962, 1644, 1607,1548, 1494 cm⁻¹ ; MS m/e 273; Analysis calc'd for C₁₇ H₂₃ NO₂ 0.20(H₂O): C, 73.72; H, 8.52; N, 5.06; found: C, 73.77; H, 8.63; N, 5.00.

Example 8 (Process 8)

Preparation of (trans)-N- 2-3-(Methylethoxy)phenyl!cyclopropyl!methyl!butanamide

To a rapidly stirred solution of (trans)-N-2-(3-hydroxyphenyl)cyclopropyl!methyl!butanamide (390 mg, 1.7 mmol),triphenylphosphine (498 mg, 1.9 mmol) and isopropanol (150 mg, 2.5 mmol)in THF (10 mL) at 0° C. was added diethyl azodicarboxylate (331 mg, 1.9mmol) in one portion. After stirring for 2 h, the suspension was dilutedwith Et₂ O (100 mL), washed with H₂ O, 2N NaOH, and brine, dried (K₂CO₃) and concentrated to a give a crude wax. The resulting material waspurified by chromatography (silica gel, 35% EtOAc/hexane) to afford 144mg (31%) of the title compound: ¹ H NMR (300 MHz, CDCl₃) δ 0.85-0.94 (m,5H), 1.22-1.24 (m, 1H), 1.29 (d, J=6.7 Hz, 6H), 1.58-1.68 (m, 2H),1.70-1.77 (m, 1H), 2.14 (t, J=6.0 Hz, 2H), 3.14-3.36 (m, 2H), 4.44-4.54(m, 1H), 5.81 (br s, 1H), 6.53-6.67 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR(NaCl Film) 3294, 2974, 1644, 1610, 1550, 1492 cm⁻¹ ; MS m/e 275;Analysis calc'd for C₁₇ H₂₅ NO₂ : C, 74.14; H, 9.15; N, 5.09; found: C,73.77; H, 8.99; N, 4.82.

Example 9 (Process 9)

9a. Preparation of (-)-(trans)-N-2-(5-Methoxy-2-phenylethynyl)phenyl!cyclopropyl!methyl!butanamide

(a) (-)-(trans)-N- 2-(5-Methoxy-2-phenylethynyl)phenylcyclopropyl!methyl!butanamide: A stirred suspension of (trans)-N-2-(2-iodo5 -methoxyphenyl) cyclopropyl!methyl!butanamide (400 mg, 1.1mmol), phenyl acetylene (133 mg, 1.3 mmol), and Pd (Ph₃ P)₄ (63 mg, 0.05mmol) in triethylamine (10 mL) was heated at reflux for 18 h, cooled toambient temperature, and diluted with Et₂ O (100 mL), washed with H₂ O,brine, dried (K₂ CO₃), and concentrated in vacuo to give 400 mg of a redoil. Purification by chromatography (silica gel, 30% EtOAc/Hexane)afforded 220 mg of a white solid (58%): mp 107°-108° C.; ¹ H NMR (300MHz, CDCl₃) δ 0.78 (t, J=7.5 Hz, 3H), 0.94-0.98 (m, 1H), 1.14-1.16 (m,2H), 1.40-1.56 (m, 2H), 1.78-1.93 (m, 2H), 2.25-2.31 (m, 1H), 2.80-2.99(m, 1H), 3.74-3.83 (m, 1H), 3.79 (s, 3H), 5.84 (br s, 1H), 6.41 (s, 1H),6.71 (d, J=4 Hz, 1H), 7.16-7.61 (m, 6H); IR (NaCl Film) 3310, 2960,2214, 1638, 1544, 1502, 1428 cm⁻¹ ; MS (ESI) m/e 347; Analysis calc'dfor C₂₃ H₂₅ NO₂ : C, 79.51; H, 7.25, N, 4.03; found: C, 79.28; H, 7.21;N, 3.78.

9b. Preparation of (-)-(trans)-N-2-(5-Methoxy-2-phenylethyl)phenyl!cyclopropyl!methyl!butanamide

(b) (-)(trans)-N-2-(5-methoxy-2-phenylethyl)phenyl!cyclopropyl!methyl!butanamide: Asuspension of (-)-(trans)-N-2-(5-methoxy-2-phenylethynyl)phenyl!cyclopropyl!methyl!butanamide (100mg, 0.28 mmol), 10% Pd/C (50 mg) in ethanol (25 mL) was shaken underhydrogen (Parr apparatus, 50 psi) for 18 h. The suspension was filteredthrough celite and concentrated in vacuo to afford a clear oil (100 mg,100%); ¹ H NMR (300 MHz, CDCl₃) δ 0.90-0.94 (m, 5H), 1.25-1.30 (m, 1H),1.60-1.66 (m, 1H), 1.71-1.79 (m, 2H), 2.05-2.15 (m, 2H), 2.88-2.98 (m,4H), 3.20-3.35 (m, 2H), 3.77 (s, 3H), 5.57 (br s, 1H), 6.47 (s, 1H),6.66-6.68 (m, 1H), 7.05 (d, J=4 Hz, 1H), 7.17-7.32 (m, 5H); IR (NaClFilm) 3294, 2960, 1644, 1548, 1498, 1454 cm⁻¹ ; MS (ESI) m/e 351;Analysis calc'd for C₂₃ H₂₉ NO₂ 0.25(H₂ O): C, 77.60; H, 8.41, N, 3.58;found: C, 77.48; H, 8.41; N, 3.58.

Example 10 (Process 10)

Preparation of (-)-(trans)-N-2-(2-Cyano-5-methoxyphenyl!cyclopropyl!methyl!butanamide

To a 100 mL round bottom flask fitted with a reflux condenser equippedwith a calcium chloride drying tube was added (trans)-N-2-(2-iodo-5-methoxyphenyl)cyclopropyl!methyl!butanamide (220 mg, 0.6mmol), powdered copper(I) cyanide (106 mg, 1.2 mmol), and anhydrouspyridine (2 mL). The mixture was then heated at 185° C. for 18 h. Thereaction was quenched by the addition of 50% aqueous ammonia solution(30 mL), followed by extraction with toluene (3×50 mL). The organicswere combined, washed with H₂ O, 1N HCl, brine, and dried over MgSO₄.Filtration and concentration in vacuo gave 310 mg of a crude oil whichwas further purified by chromatography (silica gel, 45% EtOAc/hexane) toafford a clear oil (120 mg, 74%): ¹ H NMR (300 MHz, CDCl₃) δ 0.93 (t,J6.0 Hz, 3H), 0.96-0.99 (m, 1H), 1.10-1.16 (m, 1H), 1.20-1.28 (m, 1H),1.64-1.71 (m, 2H), 2.03-2.10 (m, 1H), 2.20 (t, J=7.8 Hz, 2H), 2.72-2.79(m, 1H), 3.82 (s, 3H), 3.85-3.92 (m, 1H), 6.27 (br s, 1H), 6.56 (s, 1H),6.73 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H); IR (NaCl Film) 3300,2964, 2218, 1646, 1606, 1564, cm⁻¹ ; MS (ESI) m/e 272; Analysis calc'dfor C₁₆ H₂₀ N₂ O₂ 0.25(H₂ O): C, 69.41; H, 7.46, N, 10.12; found: C,69.41; H, 7.46; N, 10.00.

Example 11 (Process 11)

Preparation of (-)-(trans)-N-2-(2-Phenyl-5-methoxyphenyl!cyclopropyl!methyl!butanamide:

To a stirred suspension of (trans)-N- 2-(2-iodo-5-methoxyphenyl)cyclopropyl!methyl!butanamide (210 mg, 0.56 mmol), barium hydroxide (265mg, 0.84 mmol), and H20 (1 mL) in DME (6 mL) was added an admix ofPd(Ph₃ P)₄ (12 mg, 0.01 mmol) and phenyl boronic acid (75 mg, 0.62 mmol)in one portion. The resulting mixture was then heated at reflux for 18h, diluted with toluene, washed with H₂ O, brine, dried over K₂ CO₃ andconcentrated in vacuo to give a red wax. Purification by chromatography(silica gel, 35% EtOAc/hexane) afforded 145 mg (85%) of clear oil: ¹ HNMR (300 MHz, CDCl₃) δ 0.69-0.76 (m, 1H), 0.89 (t, J=7.2 Hz, 3H),0.93-0.98 (m, 1H), 1.01-1.08 (m, 1H), 1.51-1.64 (m, 2H), 1.79-1.86 (m,1H), 2.01 (t, J=7.2 Hz, 2H), 2.78-2.86 (m, 1H), 3.21-3.30 (m, 1H), 3.79(s, 3H), 5.04 (br s, 1H), 6.50 (s, 1H), 6.74 (d, J=8.4 Hz, 1H), 7.12 (d,J=8.5 Hz, 1H), 7.30-7.43 (m, 5H); IR (NaCl Film) 3296, 2962, 1644, 1610,1550, 1482, cm⁻¹ ; MS (ESI) m/e 323; Analysis calc'd for C₂₁ H₂₅ NO₂0.5(H₂ O): C, 75.87; H, 7.88, N, 4.21; found: C, 75.95; H, 7.86; N,4.15.

Example 12 (Process 12)

Preparation of (±)-(trans)-2,2-Difluoro-3-(3-methoxyphenyl)-cyclopropylmethyl!butanamide

Step i

(a) (±)-(trans)-3-(3-Methoxyphenyl)-prop-2-en-1-ol: A solution of3-methoxycinnamic acid (50.24 g, 281 mmol) in 400 mL of anhydroustetrahydrofuran was added to a magnetically stirred suspension of sodiumborohydride (12.80 g, 338 mmol) in 500 mL of anhydrous tetrahydrofuranat room temperature. The suspension was stirred until gas evolutionceased, cooled to 0° C., and a solution of iodine (35.77 g, 141 mmol) inanhydrous tetrahydrofuran (500 mL) was added over 1 h. The suspensionwas stirred for 3 h and treated dropwise with a 4N solution ofhydrochloric acid (100 mL). The resultant suspension was extracted withdiethyl ether (3×500 mL), and the combined organic portions washed with3N NaOH (3×500 mL), brine (500 mL), dried (MgSO₄), filtered, andconcentrated in vacuo. Kugelrohr distillation (0.5 mm) gave the productas a clear liquid (23.12 g, 50%): ¹ H NMR (300 MHz, CDCl₃) δ 3.82 (s,3H), 4.34 (d, J=6 Hz, 2H), 6.37 (dt, J=15,6 Hz, 1H), 6.60 (d, J=15 Hz,1H), 6.80 (dd, J=8, J=1 Hz, 1H), 6.93 (t, J=1 Hz, 1H), 7.00 (d, J=8 Hz,1H), 7.24 (t, J=8 Hz, 1H).

Step ii

(b) (±)-(trans)-Acetic acid (3-(3-methoxyphenyl) allyl ester: Amagnetically stirred solution of(±)-(trans)-3-(3-Methoxyphenyl)-prop-2-en-1-ol (22.35 g, 136 mmol) inanhydrous pyridine (115 mL) at 0° C. was treated dropwise with aceticanhydride (16.0 mL, 170 mmol). After addition was complete the ice bathwas removed, the solution was allowed to warm to room temperature, andstirred for 24 h. The solution was concentrated in vacuo and the residuedigested with diethyl ether (300 mL), washed with 1N HCl (2×300 mL), 5%NaHCO₃ (200 mL), water (200 mL), brine (200 mL), dried over MgSO₄,filtered, and concentrated in vacuo to a clear liquid. Flashchromatography (5% diethyl ether/hexane elution) and Kugelrohrdistillation (0.5 mm) of the resultant liquid gave the product as aclear liquid (16.95 g, 60%): ¹ H NMR (300 MHz, CDCl₃) δ 2.11 (s, 3H),3.81 (s, 3H), 4.73 (d, J=6 Hz, 2H), 6.28 (dt, J=15.6 Hz, 1H), 6.63 (d,J=15 Hz, 1H), 6.82 (dd, J=8, 1 Hz, 1H), 6.92(t, J=1 Hz, 1H), 6.99(d, J=8Hz, 1H), 7.24(t, J=8Hz, 1H).

Step iii

(c) (±)-(trans)-Acetic acid-2,2-difluoro-3-(3-methoxyphenyl)cyclopropylmethyl ester: A solution of (±)-(trans)-Acetic acid (3-(3-methoxyphenyl)allyl ester (1.63 g, 7.90 mmol) in anhydrous diglyme was heated atreflux and subsequently treated dropwise over 1 h with a solution ofsodium chlorodifluoroacetate (9.02 g, 59.2 mmol) in anhydrous diglyme(25 mL). The suspension was cooled to room temperature and poured over200 mL of ice. The resultant suspension was extracted with diethyl ether(4×200 mL) and the combined organic extracts were washed with water(3×400 mL), brine (400 mL), dried (MgSO₄), filtered, and concentrated invacuo. Kugelrohr distillation (0.5 mm) gave 1.59 g (79%) of the productas a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ 2.10 (s, 3H), 2.24 (ddt,J=15, 7.5, 7 Hz, 1 H), 2.63 (dd J=15, 7.5 Hz, 1H), 3.80 (s, 3H),4.19-4.25 (m, 1H), 4.31-4.37 (m, 1H), 6.7-6.83 (m, 3H), 7.25 (t, J=8 Hz,1H).

Step iv

(d) (±)-(trans)- 2,2-Difluoro-3-(3-methoxyphenyl)cyclopropyl!methanol: Amagnetically stirred solution of potassium hydroxide (2.39 g, 42.6 mmol)in 3:1 methanol/tetrahydrofuran (88 mL) was treated with(±)-(trans)-acetic acid-2,2-difluoro-3-(3-methoxyphenyl)cyclopropylmethyl ester (4.16 g, 16.2 mmol). The solution was stirred for 2 h andconcentrated in vacuo. The residue was digested with diethyl ether (200mL) and water (200 mL), the layers separated, the aqueous layer furtherextracted with diethyl ether (2×200 mL), the organic extracts washedwith saturated NaHCO₃ solution (300 mL), water (300 mL), brine (300 mL),dried (MgSO₄), filtered, and concentrated in vacuo to give 3.42 g (99%)of a clear oil that was used without further purification: ¹ H NMR (300MHz, CDCl₃) δ 1.60 (br s, 1H), 2.15-2.36 (m, 1 H), 2.60 (ddd, J=15, 7.5,1.5 Hz, 1H), 3.81 (s, 3H), 3.83-3.98 (m, 2H), 6.77 (t, J=1 Hz, 1H), 6.81(d, J=8 Hz, 1H), 6.82 (dd, J=8, 1 Hz, 1H), 7.26 (t, J=8 Hz, 1H).

Step v

(e)(f)(g) (±)-(trans)-2,2-Difluoro-3-(3-methoxyphenyl)cyclopropyl!methanamine: A magneticallystirred solution of the alcohol (3.27 g, 15.3 mmol), triethylamine (3.14g, 31.0 mmol), and CH₂ Cl₂ (50 mL) at 0° C. under nitrogen was treateddropwise over 15 min with methanesulfonyl chloride (2.8 g, 24.4 mmol).The solution was stirred 30 min, diluted with CH₂ Cl₂ (200 mL), andwashed sequentially with water (200 mL) and saturated NaHCO₃ (200 mL),dried (K₂ CO₃), filtered, and concentrated in vacuo at 5° C. The residuewas digested with anhydrous dimethylformamide (50 mL), treated withsodium azide (1.96 g, 30.1 mmol), and stirred 14 h. The resultantsolution was poured into water (500 mL), extracted with diethyl ether(4×250 mL), the combined extracts washed with water (4×500 mL), brine(2×300 mL), dried (MgSO₄), filtered, and concentrated in vacuo(caution|) to a clear oil. The oil was digested with anhydrous diethylether (40 mL) and added dropwise to a magnetically stirred suspension oflithium aluminum hydride (1.16 g, 30.6 mmol) in anhydrous diethyl ether(60 mL) at -30° C. The suspension was allowed to warm to roomtemperature, stirred for 3 h, recooled to -30° C., and treated dropwisewith a solution of KHSO₄ (2.6 g, 19 mmol) in water (20 mL). Theresultant suspension was allowed to warm to room temperature, stirred 1h, and filtered through celite with diethyl ether elution (400 mL). Thelayers were separated and the organic layer extracted with 1N HCl (3×100mL), the combined aqueous extracts made basic with 50% NaOH, andextracted with CH₂ Cl₂ (3×150 mL). The organic portion was washed withbrine (200 mL), dried (K₂ CO₃), filtered, and concentrated in vacuo togive 1.23 g (38%) of a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ 1.42 (br s,2H), 1.97-2.08 (m, 1 H), 2.44-2.52 (m, 1H), 2.91-3.10 (m, 2 H), 3.80 (s,3H), 6.76 (t, J=1 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.81 (dd, J=8, 1 Hz,1H), 7.23 (t, J=8 Hz, 1H).

Step vi

(h) (±)-(trans)-2,2-Difluoro-3-(3-methoxyphenyl)cyclopropylmethyl!butanamide: Amagnetically stirred solution of (±)-(trans)-2,2-Difluoro-3-(3-methoxyphenyl)-cyclopropyl!methanamine (672 mg, 3.16mmol) and triethylamine (1.5 mL) in anhydrous CH₂ Cl₂ (20 mL) wastreated dropwise with a solution of butyryl chloride (370 mg, 3.47 mmol)in anhydrous CH₂ Cl₂ (3 mL). The solution was stirred for 48 h andconcentrated in vacuo. The residue was digested with CH₂ Cl₂ (100 mL)and washed with 1N HCl (100 mL), 1N NaOH (100 mL), brine (100 mL), dried(K₂ CO₃), filtered, and concentrated in vacuo. Flash chromatography (2:1hexanes/ethyl acetate elution) gave the product as a clear oil thatsolidified to a waxy solid on standing: ¹ H NMR (300 MHz, CDCl₃) δ 0.92(t, J=7.4 Hz, 3H), 1.64 (sextet, J=7.4 Hz, 2H), 2.09-2.21 (m, 1 H), 2.16(t, J=7.4 Hz, 2H), 2.51 (dd, J=13.8, 7.4 Hz, 1H), 3.19-3.22 (m, 1 H),3.76 (s, 3H), 3.77-3.85 (m, 1H), 5.90 (br s, 1H), 6.70 (s, 1H), 6.75 (d,J=8 Hz, 1H), 6.77 (dd, J=8, 1 Hz, 1H), 7.20 (t, J=8 Hz, 1H); IR (NaClFilm) 3302, 2960, 1644, 1552, 1288, 1266, 1250, 1160 cm⁻¹ ; MS(isobutane-DCI) m/e 282 (M-H⁻); Analysis calc'd for C₁₅ H₁₉ NO₂ F₂ : C,63.59; H, 6.76; N, 4.94; found: C, 63.59; H, 6.83; N, 4.85.

Example 13 (Process 13)

Preparation of (trans)-N-2-(2-Butyrylamino-5-methoxyphenyl)cyclopropyl!methyl!butanamide

Step i

(a) (trans)-N- 2-(2-Amino-5-methoxyphenyl)cyclopropane!methyl!amine: AParr bottle was charged with a suspension of(trans)-2-(2-nitro-5-methoxyphenyl)cyclopropane carboxaldehyde oxime(1.0 g, 4.2 mmol), 10% Pd/C (100 mg) and HOAc (25 mL) was shaken underhydrogen (50 psi) for 18 h. The material was then filtered throughcelite, digested with H₂ O (300 mL) and made basic with 10N NaOH. Theproduct was then extracted with CH₂ Cl₂, the extracts were combined,dried over K₂ CO₃, and concentrated in vacuo to afford 800 mg (100%) ofa red oil: ¹ H NMR (300 MHz, CDCl₃) δ 0.78-0.85 (m, 1H), 1.34-1.39 (m,1H), 1.59-1.69 (m, 1H), 1.77-1.83 (m, 1H), 1.88 (br s, 2H), 3.10-3.38(m, 2H), 3.66 (s, 3H), 6.39 (d, J=6.0 Hz, 1H), 6.50-6.59 (m, 1H), 6.61(br s, 2H), 6.78-6.97 (m, 1H).

Step ii

(b) (trans)-N- 2-(2-Butyrylamino-5-methoxyphenyl)cyclopropyl!methyl!-butanamide: To a magneticallystirred solution of (trans)-N2-(2-amino-5-methoxyphenyl)cyclopropane!methyl!amine (400 mg, 2.2 mmol)and Et₃ N (0.86 mL, 6.6 mmol) in dry CH₂ Cl₂ (15 mL) at 0° C. was addedbutyryl chloride (256 mg, 2.4 mmol) dropwise. The resulting suspensionwas allowed to come to room temperature and stirred for 18 h.Concentration by rotary evaporation yielded a crude product which wasthen purified by flash chromatography (silica gel, 30% EtOAc/hexane) toafford 250 mg (44% ) of a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ0.75-1.04 (m, 8H), 1.50-1.76 (m, 5H), 2.10 (t, J=8.1 Hz, 2H), 2.45 (t,J=8.0 Hz, 2H), 2.68-2.78 (m, 1H), 3.69 (s, 3H), 3.72-3.78 (m, 2H), 6.27(d, J=2.0 Hz, 1H), 6.36 (br s, 1H), 6.63 (dd, J=7.8, 2.7 Hz, 1H), 7.50(d, J=8.7 Hz, 1H), 7.89 (br s, 1H); IR (NaCl Film) 3290, 2961, 1647,1534, 1425 cm⁻¹ ; MS (ESI) m/e 332; Analysis calc'd for C₁₉ H₂₈ N₂O₃.0.4 H₂ O: C, 67.19; H, 8.54; N, 8.24; found: C, 67.58; H, 8.19; N,7.77.

Example 14 (Process 14)

Preparation of (-)-(trans)-N- 1-2-(3-Methoxyphenyl)cyclopropyl!ethyl!butanamide (Isomer A)

Step i

(a) (-)-(trans)-1- 2-(3-Methoxyphenyl)cyclopropyl!ethanol (Isomer A) and(-)(trans)-1- 2-(3-Methoxyphenyl)cyclopropyl!ethanol (Isomer B):

Dimethyl sulfoxide (3.98 mL, 56 mmol) was added dropwise to a solutionof oxalyl chloride (2M in CH₂ Cl₂, 19.5 mL, 39 mmol) in methylenechloride (20 mL) at -78° C. A solution of (-)-(trans)2-(3-Methoxyphenyl)cyclopropyl!methanol (5.0 g, 28 mmol) indichloromethane (10 mL) was added dropwise. The solution was stirred for30 min, triethylamine (16.2 mL, 112 mmol) was slowly added, and theresulting suspension allowed to warm to room temperature. The suspensionwas stirred for 30 min, diluted with CH₂ Cl₂ (100 mL), washed withwater, dried over K₂ CO₃, and concentrated in vacuo to afford 5.8 g ofthe aldehyde, which was used without purification The aldehyde wasdigested with THF (10 mL) and added dropwise to a solution of methylmagnesium bromide (3M in Et₂ O, 23.3 mL, 70 mmol) in THF (25 mL) at 0°C. The solution was stirred at 0° C. for 2 h after which 2N HCl (20 mL)in EtOAc (250 mL) was added. The resultant suspension was then washedwith H₂ O, brine, dried (K₂ CO₃), and concentrated in vacuo to give 5.5g of a crude oil. Purification by silica gel chromatography (25%EtOAc/hexane) afforded two diastereomers, (isomer A) 1.66 g, 1st band,and (isomer B) 1.64 g, 2nd band: (isomer A) R_(f) =0.45 (25%EtOAc/hexanes); ¹ H NMR (300 MHz, CDCl₃) δ 0.84-0.94 (m, 2H), 1.19-1.27(m, 1H), 1.30 (d, J=6.3 Hz, 3H), 1.83-2.02 (m, 1H), 3.32-3.38 (m, 1H),3.77 (s, 3), 6.60-6.73 (m, 3H), 7.12 (t, J=7.8 Hz, 1H); a!_(D) ²⁰ -49.0°(c=1, CH₂ Cl₂). (isomer B) R_(f) =0.40 (25% EtOAc/hexanes); 1H NMR (300MHz, CDCl₃) δ 0.93-1.00 (m, 2H), 1.21-1.29 (m, 1H), 1.32 (d, J=6.3 Hz,3H), 1.75-1.78 (m, 1H), 3.33-3.38 (m, 1H), 3.77 (s, 3H), 6.59-6.69 (m,3H), 7.15 (t, J=7.8 Hz, 1H); a!D²⁰ -55.3° (c=1, CH₂ Cl₂).

Step ii

(b) (-)-(trans)-2- 1-2-(3-methoxyphenyl)cyclopropyl!ethyl!isoindole-1,3-dione isomerA):Diethyl azodicarboxylate (1.79 g, 10.3 mmol) was added dropwise to astirred solution of (-)-(trans)-1-2-(3-methoxyphenyl)cyclopropyl!ethanol (isomer A) (1.66 g, 8.6 mmol),triphenyl phosphine (2.69 g, 10.3 mmol), and phthalimide (1.52 g, 10.3mmol) in THF (75 mL) at 0° C. The reaction was allowed to warm toambient temperature and stirred for 18 h. The solvent was removed invacuo and the resulting residue was digested with EtOAc (150 mL) andwashed sequentially with 1N HCl, 1N NaOH, and brine. Drying over K₂ CO₃,filtration, and concentration in vacuo afforded 2.6 g (94%) of theproduct as a waxy white solid: ¹ H NMR (300 MHz, CDCl₃) δ 0.80-0.92 (m,2H), 1.48-1.60 (m, 4H), 1.81-1.88 (m, 1H), 1.91-2.00 (m, 1H), 3.76 (s,3H), 6.58-6.70 (m, 3H), 7.15 (t, J=7.8 Hz, 1H), 7.24-7.80 (m, 4H).

Step iii

(c) (-)-(trans)-1- 2-(3-Methoxyphenyl)cyclopropyl!ethylamime (isomer A):A solution of (-)-(trans)-2- 1-2-(3-methoxyphenyl)cyclopropyl!ethyl!isoindole-1,3-dione (isomer A) (2.6g, 8.1 mmol) and hydrazine (827 mg, 25.8 mmol) in ethanol (75 mL) wasstirred at room temperature for 18 h. The resultant white paste wasdiluted with ethanol (100 mL), treated with 10N HCl (10 mL), and stirredfor 1 h. The solution was treated with EtOAc (200 mL), and extractedwith 1N HCl. The acidic extracts were combined, washed with Et₂ O,basified (10N NaOH), and extracted with CH₂ Cl₂. The organics were driedover K₂ CO₃ and concentrated in vacuo to give 1.1 g of a crude oil.Purification by silica gel chromatography (10% MeOH/CH₂ Cl₂) afforded aclear oil (600 mg, 40%): ¹ H NMR (300 MHz, CDCl₃) δ 0.85-0.98 (m, 2H),1.10-1.20 (m, 1H), 1.25 (d, J=6.0 Hz, 3H), 1.70-1.79 (m, 1H), 2.30 (brs, 2H), 2.48-2.52 (m, 1H), 3.75 (s, 3H), 6.58-6.75 (m, 3H), 7.15 (t,J=7.0 Hz, 1H).

Step iv

(d) (-)-(trans)-N- 1- 2-(3-Methoxyphenyl)cyclopropyl!ethyl!butanamide(isomer A): To a magnetically stirred solution of (-)-(trans)-1-2-(3-methoxyphenyl)cyclopropyl!ethylamine (isomer A) (200 mg, 1.1 mmol)and Et₃ N (0.46 mL, 3.3 mmol) in dry dichloromethane (15 mL) at 0° C.was added butyryl chloride (127 mg, 1.2 mmol) dropwise. The resultingsuspension was allowed to warm to room temperature and stirred for 4 h.The solvent was removed in vacuo and the residue was digested with EtOAc(100 mL), washed sequentially with H₂ O, 5% citric acid, 5% K₂ CO₃,brine, and dried over K₂ CO₃. Filtration and concentration in vacuoyielded a crude product which was then purified by flash chromatography(silica gel, 40% EtOAc/hexane) to afford 100 mg (39%) of the titlecompound: R_(f) =0.75 (10% MeOH/CHCl₃); ¹ H NMR (300 MHz, CDCl₃) δ0.85-0.97 (m, 4H), 1.04-1.17 (m, 2H), 1.24 (d, J=6.6 Hz, 3H), 1.61-1.73(m, 2H), 1.77-1.83 (m, 1H), 2.19 (t, J=7.8 Hz, 2H), 3.54-3.68 (m, 1H),3.77 (s, 3H), 5.59 (s, 1H), 6.57-6.71 (m, 3H), 7.15 (t, J=7.6 Hz, 1H);IR (NaCl Film) 3291, 2963, 1640, 1543, 1455 cm⁻¹ ; MS (ESI) m/e 261;Analysis calc'd for C₁₆ H₂₃ NO₂ : C, 73.53; H, 8.87; N, 5.36; found: C,73.48; H, 8.86; N, 5.25.

Example 15 (Process 15)

Preparation of (trans)-N- 2-3-(Methylethoxy)phenyl!cyclopropyl!methyl!butanamide

A solution of (trans)-N-2-(3-hydroxyphenyl)cyclopropyl!methyl!butanamide (342 mg, 1.47 mmol) andsodium hydroxide (58 mg, 1.45 mmol) in anhydrous methanol (10 mL) wasconcentrated in vacuo and the residue powdered under anhydrous toluene(3 mL). The suspension was treated with a solution of ethylene carbonate(259 mg, 2.94 mmol) in anhydrous toluene (5 mL). The resultant mixturewas heated at reflux for 12 h, cooled to room temperature, and treatedwith 3N NaOH (100 mL), ice (50 g), and diethyl ether (100 mL). Theaqueous layer was separated and extracted with fresh diethyl ether(2×100 mL). The combined organic extracts were washed with water (200mL), brine (200 mL), dried (K₂ CO₃), filtered, and concentrated invacuo. Flash chromatography of the resultant oil (1:2 hexane/ethylacetate) gave 178 mg (44%) of the compound as a clear oil: ¹ H NMR (300MHz, CDCl₃) δ 0.84-0.92 (m, 2H), 0.91 (t, J=7.4 Hz, 2H), 1.21-1.32 (m,1H), 1.63 (sextet, J=7.4 Hz, 2H), 1.72-1.78 (m, 1H), 2.13 (t, J=7.4 Hz,2H), 2.30 (br s, 1H), 3.16-3.34 (m, 2H), 3.91 (t, J=4.5 Hz, 2H), 4.03(t, J=4.5 Hz, 2H), 5.75 (br s, 1H), 6.58 (t, J=1.5 Hz, 1H), 6.63 (d,J=8.0 Hz, 1H), 6.68 (ddd, J=8.0, 1.5, 1.5 Hz, 1 H), 7.13 (t, J=8.0 Hz,1H); IR (NaCl Film) 3300, 3076, 2962, 1644, 1610, 1582, 1552 cm⁻¹ ; MSm/e 276 (M-H⁻); Analysis calc'd for C₁₆ H₂₃ NO₃ : C, 69.29; H, 8.36; N,5.05; found: C, 68.99; H, 8.39; N, 4.93.

Example 16 (Process 16)

Preparation of (-)-(trans)-N-2-(3-Methoxyphenyl)cyclopropyl!ethyl!-butanamide

Step i

(a) (-)-(trans)-1-(Cyanomethyl)-2-(3-methoxyphenyl)cyclopropane: To amagnetically stirred solution of(-)-(trans)-2-(3-methoxyphenyl)cyclopropane methanol (1.60 g, 8.8 mmol)and triethylamine (1.9 mL, 13.2 mmol) in dichloromethane (150 mL) at 0°C. was added methanesulfonyl chloride (1.21 g, 10.6 mmol) dropwise.After addition was complete the ice bath was removed and stirring wascontinued for 1 h. The solution was treated with dichloromethane (150mL), washed with saturated NaHCO₃, and dried over K₂ CO₃. Concentrationin vacuo gave 1.78 g of a crude oil which was utilized without furtherpurification.

The mesylate was taken into DMF (100 mL), treated with sodium cyanide(862 mg, 17.6 mmol), and stirred on a steam bath for 4 h. The solutionwas concentrated in vacuo, the residue was taken into Et₂ O (100 mL),washed with H₂ O, brine, and the solvent removed in vacuo to produce1.41 g (85%,) of a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ 0.90-1.09 (m,2H), 1.23-1.30 (m, 1H), 1.81-1.92 (m, 1H), 2.52-2.60 (m, 2H), 3.78 (s,3H), 6.58-6.72 (m, 3H), 7.19 (t, J=8.0 Hz, 1H).

(b) (-)-(trans)-2-(3-Methoxyphenyl)cyclopropane ethylamine: To a stirredsuspension of LiAlH₄ (650 mg, 17 mmol) in THF (50 mL) at 45° C. wasadded a solution of(-)-(trans)-1-(cyanomethyl)-2-(3-methoxyphenyl)cyclopropane (1.41 g, 7.5mmol) in THF (25 mL). The temperature was maintained below -30° C.,throughout. After addition was complete, the suspension was allowed towarm to room temperature and stirred for 4 h. The suspension wasrecooled to -45° C. and 1N HCl (50 mL) was cautiously added dropwise.The suspension was stirred at room temperature for 30 min, filteredthrough celite, and the filter cake was washed well with Et₂ O. Thefiltrates were combined, extracted with 1N HCl, and the acidic layerswere basified (30% NaOH). The basic solution was extracted with CH₂ Cl₂,dried (K₂ CO₃), and concentrated in vacuo to afford 500 mg (39%) of aclear oil: ¹ H NMR (300 MHz, CDCl₃) δ 0.75-0.82 (m, 1H), 0.88-0.96 (m,1H), 1.00-1.11 (m, 1H), 1.45-1.70 (m, 3H), 2.62 (br s, 2H), 2.88 (t,J=7.5 Hz, 2H), 3.77 (s, 3H), 6.52-6.70 (m, 3H), 7.18 (t, J=8.0 Hz, 1H).

(c) (-)-(trans)-N- 2-(3-Methoxyphenyl)cyclopropyl!ethyl!butanamide: To amagnetically stirred solution of (-)-(trans)-2-(3-methoxyphenyl)cyclopropane ethylamine (400 mg, 2.2 mmol) and Et₃ N (0.86 mL, 6.6 mmol)in dry dichloromethane (15 mL) at 0° C. was added butyryl chloride (256mg, 2.4 mmol) dropwise. The resulting suspension was allowed to come toroom temperature and stirred for 18 h. Concentration in vacuo yielded acrude product which was then purified by flash chromatography (silicagel, 30% EtOAc/hexane) to afford 250 mg (44% ) of a clear oil: ¹ H NMR(300 MHz, CDCl₃) δ0.70-0.81 (m, 1H), 0.88-1.01 (m, 5H), 1.54-1.68 (m,5H), 2.12 (t, J=7.2 Hz, 2H), 3.29-3.36 (m, 2H), 3.77 (s, 3H), 5.75 (brs, 1H), 6.54-6.71 (m, 3H), 7.14 (t, J=7.8 Hz, 1H); IR (NaCl Film) 3295,2962, 1644, 1604, 1551, 1494 cm⁻¹ ; MS (ESI) m/e 261; a!_(D) ²⁰ -66.3°(c=1, CH₂ Cl₂); Analysis calc'd for C₁₆ H₂₃ NO₂.0.20 H₂ O: C, 72.53; H,8.90; N, 5.29; found: C, 72.67; H, 9.03; N, 5.29.

Example 17 (Process 17)

Preparation of (trans)-N-3-(3-methoxyphenyl)-2,2-dimethyl-1-cyclopropyl!methyl!butanamide.

Step i

(a) (trans)-3-(3-Methoxypheny)-2,2-dimethyl-cyclopropane carboxylic acidethyl ester: To a stirred solution of isopropyltriphenylphosphoniumiodide (50 g, 116 mmol) in THF (250 mL) at 0° C. was added butyllithium(2.3M in hexane, 42.2 mL, 115.6 mmol) dropwise, maintaining thetemperature below 5° C. throughout. The solution was stirred for 1 h,treated dropwise with a solution of cinnamic acid ethyl ester (18.33 g,89 mmol) in THF (50 mL), allowed to warm to room temperature, andstirred for 4 h. The resulting suspension was quenched with saturatedNH₄ Cl (200 mL), and extracted with ethyl acetate. The organic extractswere combined, washed with brine, dried (K₂ CO₃), and concentrated togive a light brown solid. This solid was then purified by Kuigelrohrdistillation (110° C., 0.5 mm) to give 13.0 g (59%) of a clear oil: ¹ HNMR (300 MHz, CDCl₃) δ 0.95 (s, 3H), 1.12 (t, J=8.5 Hz, 3H), 1.38 (s,3H), 1.95 (d, J=6.0 Hz, 1H), 2.62 (d, J=6.0 Hz, 1H), 3.80 (s, 3H), 4.12(q, J=7.0 Hz, 2H), 6.65-6.68 (m, 2H), 7.18-7.26 (m, 2H).

Step ii

(b) (trans)-(3-(3-Methoxyphenyl)-2,2-dimethyl-cyclopropyl) methanol: Toa suspension of LiAlH₄ (4.21 g, 111 mmol) in THF (200 mL) at -45° C. wasadded a solution of (trans)-3-(3-methoxypheny)-2,2-dimethyl-cyclopropanecarboxylic acid ethyl ester (12.5 g, 50.4 mmol) in THF (20 mL) dropwise.The cooling bath was then removed and the reaction was allowed to cometo room temperature followed by immediate recooling to -45° C. Asolution of KHSO₄ (24 g, 177 mmol) in H₂ O(50 mL) was cautiously addedallowing the temperature to rise to -5° C. The resulting paste wasstirred at room temperature for 1 h, filtered through celite, and thefilter cake was washed with Et₂ O. The combined filtrates were washedwith cold (0 ° C.) 1N HCl (3×), 5% K₂ CO₃ (1×), brine (1×), dried (K₂CO₃), and concentrated to give 10.1 g (97%) of a clear oil: ¹ H NMR (300MHz, CDCl₃) δ 0.85 (s, 3H), 1.25 (s, 3H), 1.78 (d, J=6.0 Hz, 1H),3.62-3.72 (m, 3H), 3.79 (s, 3H), 3.82 (dd, J=7, 10 Hz, 1H), 6.70-6.78(m, 2H), 7.20 (t, J=7.5 Hz, 1H), 7.35 (m, 1H).

Step iii

(c) (trans)-(3-(3-Methoxyphenyl)-2,2-d imethyl-cyclop ropyl)methyl)azide: To a solution of(trans)-(3-(3-methoxyphenyl)-2,2-dimethyl-cyclopropyl) methanol (10.0 g,48.5 mmol) and triethylamine (10.1 mL, 72.8 mmol), in dichloromethane(100 mL) at 0° C. was added methanesulfonyl chloride (6.11 g, 53.4 mmol)dropwise. After addition was complete the ice bath was removed andstirring was continued for 30 min. The reaction was then diluted withdichloromethane (100 mL), washed with H₂ O, saturated NaHCO₃, and driedover K₂ CO₃. Concentration in vacuo gave 13.09 g of a colored oilsuitable for use in the next step.

The above mesylate was taken into DMF (100 mL), treated with sodiumazide (3.78 g, 58.2 mmol), and stirred at room temperature for 18 h. Themixture was concentrated and the residue was taken into Et₂ O, washedwith H₂ O (1×), brine(1×), and the solvents removed in vacuo to produce10.1 g of a clear oil suitable for use without further purification: ¹ HNMR (300 MHz, CDCl₃) δ 0.85 (s, 3H), 1.30 (s, 3H), 1.39-1.42 (m, 1H),1.80 (d, J=6.0 Hz, 1H), 3.30 (dd, J=8, 10 Hz, 1H), 3.51 (dd, J=6.0, 8.3Hz, 1H), 3.80 (s, 3H), 6.68-6.79 (m, 3H), 7.20 (t, J=7.5 Hz, 1H).

Step iv

(d) (trans)-(3-(3-Methoxyphenyl)-2,2-dimethyl-cyclopropyl)methyl) amine:A stirred suspension of LiAlH₄ (4.80 g, 126.6 mmol) in THF (100 mL) at-30° C. was treated with a solution of(trans)-(3-(3-methoxyphenyl)-2,2-dimethyl-cyclopropyl)methyl) azide(6.48 g, 30.14 mmol) in THF (10 mL), maintaining the temperature below-30° C. After addition was complete the suspension was allowed to cometo room temperature and stirred for 4 h. The suspension was cooled to-45°C. and a solution of KHSO₄ (16 g) in H₂ O (20 mL) was added dropwise(caution|). The resulting suspension was stirred at room temperature for30 min, filtered through celite, and the filter cake was washed wellwith Et₂ O. The filtrates were combined, extracted with 1N HCl (2×), andthe acidic layers were basified (30% NaOH). The basic solution wasextracted with CH₂ Cl₂ (3×), dried (K₂ CO₃), and concentrated to afford2.80 g (47%) of a clear oil: ¹ H NMR (300 MHz, CDCl₃) δ 0.82 (s, 3H),1.22 (s, 3H), 1.60-1.68 (m, 4H), 2.75-2.92 (m, 2H), 3.78 (s, 3H),6.68-6.75 (m, 3H), 7.15 (t, J=7.5 Hz, 1H).

Step v

(e) (trans)-N-3-(3-methoxyphenyl)-2,2-dimethyl-1-cyclopropyl!methyl!butanamide:Acylation of (3-(3-methoxyphenyl)-2,2-dimethyl-cyclopropyl)-methyl)amine (620 mg, 3.0 mmol) as in Example 1 was accomplished with butyrylchloride (0.34 mL, 3.3 mmol) to give 550 mg (67%) of a clear oil: ¹ HNMR (300 MHz, CDCl₃) δ 0.80 (s, 3H), 0.90 (t, J=7.4 Hz, 3H), 1.23 (s,3H), 1.23-1.30 (m, 1H), 1.58-1.71 (m, 3H), 2.14 (t, J=7.3 Hz, 2H), 3.39(t, J=5.4 Hz, 2H), 3.76 (s, 3H), 5.50 (br s , 1H), 6.65-6.71 (m, 3H),7.15 (t, J=7.8 Hz, 1H); IR (NaCl Film) 3294, 2964, 1642, 1550, 1490,1456, 1274 cm⁻¹ ; MS m/e 275.39; Analysis calc'd for C₁₇ H₂₅ NO₂ : C,74.14; H, 9.15; N, 5.09; found: C, 73.95; H, 9.21; N, 5.11.

Table 1 shows chemical data for compounds of Formula I wherein X isOCH₃, R is hydrogen, G is methylene and the other substituents are asindicated below.

                                      TABLE 1    __________________________________________________________________________     ##STR23##    Ex.       Opt.          Prep.                                  Elemental analysis    No.*       Ism.          Process              Y Z         R.sub.1                            R.sub.2   Compound Formula                                                 Calc'd                                                      Found    __________________________________________________________________________    1  +/-          1   H F         H CH(CH.sub.3).sub.2                                      C.sub.15 H.sub.20 NO.sub.2 F                                                 C, 67.90                                                      C, 68.18                                                 H,  7.60                                                      H,  7.77                                                 N,  5.28                                                      N,  5.24    2  +/-          2   H H         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.21 NO.sub.2                                                 C, 72.84                                                      C, 72.71                                                 H,  8.56                                                      H,  8.50                                                 N,  5.66                                                      N,  5.62     3a       +  3   H H         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.21 NO.sub.2.0.1H.sub.2                                                 C, 72.31                                                      C, 72.30                                                 H,  8.58                                                      H,  8.52                                                 N,  5.62                                                      N,  5.59     3b       -  3   H H         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.21 NO.sub.2                                                 C, 72.84                                                      C, 72.77                                                 H,  8.56                                                      H,  8.52                                                 N,  5.66                                                      N,  5.62    4  +/-          4   H I         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.20 NO.sub.2 I                                                 C, 48.27                                                      C, 48.24                                                 H,  5.40                                                      H,  5.41                                                 N,  3.75                                                      N,  3.53    5  -  5   Br                Br        H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.19 NO.sub.2 Br.sub.2                                                 C, 44.47                                                      C, 44.59                                                 H,  4.73                                                      H,  4.65                                                 N,  3.46                                                      N,  3.16    6  +/-          6   H H         Bn                            CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.22 H.sub.27 NO.sub.2.0.1H.sub.2                                                 C, 77.88                                                      C, 77.87                                                 H,  8.08                                                      H,  8.12                                                 N,  4.13                                                      N,  3.89     9a       +   9a H PhCC      H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.23 H.sub.25 NO.sub.2                                                 C, 79.51                                                      C, 79.28                                                 H,  7.25                                                      H,  7.21                                                 N,  4.03                                                      N,  3.78     9b       -   9b H PhCH.sub.2 CH.sub.2                          H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.23 H.sub.29 NO.sub.2.0.25(H.sub.2                                      O)         C, 77.60                                                      C, 77.48                                                 H,  8.41                                                      H,  8.41                                                 N,  3.58                                                      N,  3.58    10 -  10  H CN        H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.16 H.sub.20 N.sub.2 O.sub.2.0.25(H                                      .sub.2 O)  C, 69.41                                                      C, 69.41                                                 H,  7.46                                                      H,  7.46                                                 N, 10,12                                                      N, 10.00    11 -  11  H Ph        H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.21 H.sub.25 NO.sub.2.0.5(H.sub.2                                      O)         C, 75.87                                                      C, 75.95                                                 H,  7.88                                                      H,  7.86                                                 N,  4.21                                                      N,  4.15    13 -  13  H NHCO(CH.sub.2).sub.2 CH.sub.3                          H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.19 H.sub.28 N.sub.2 O.sub.3.0.4(H.                                      sub.2 O)   C, 67.19                                                      C, 67.58                                                 H,  8.54                                                      H,  8.19                                                 N,  8.24                                                      N,  7.77    18 +/-          2   H H         H CH.sub.2 CH.sub.3                                      C.sub.14 H.sub.19 NO.sub.2                                                 C, 72.07                                                      C, 71.83                                                 H,  8.21                                                      H,  8.15                                                 N,  6.00                                                      N,  5.80    19 +/-          2   H H         H CH.sub.3  C.sub.13 H.sub.17 NO.sub.2                                                 C, 71.20                                                      C, 71.01                                                 H,  7.81                                                      H,  7.77                                                 N,  6.39                                                      N,  6.33    20 +/-          2   H H         H CH.sub.2 OCH.sub.3                                      C.sub.14 H.sub.19 NO.sub.3                                                 C, 67.45                                                      C, 67.14                                                 H,  7.68                                                      H,  7.85                                                 N,  5.62                                                      N,  5.60    21 +/-          2   H H         H CH(CH.sub.3).sub.2                                      C.sub.15 H.sub.21 NO.sub.2                                                 C, 72.84                                                      C, 72.64                                                 H,  8.56                                                      H,  8.52                                                 N,  5.66                                                      N,  5.61    22 -  3   H H         H CH(CH.sub.3).sub.2                                      C.sub.15 H.sub.21 NO.sub.2                                                 C, 72.84                                                      C, 72.69                                                 H,  8.56                                                      H,  8.50                                                 N,  5.66                                                      N,  5.51    23 +/-          2   H H         H CH.sub.2 SCH.sub.3                                      C.sub.14 H.sub.19 NO.sub.2 S                                                 C, 63.37                                                      C, 62.97                                                 H,  7.22                                                      H,  7.05                                                 N,  5.28                                                      N,  5.02    24 +/-          2   H H         H NHCH.sub.2 CH.sub.3                                      C.sub.14 H.sub.20 N.sub.2 O.sub.2.0.6H.s                                      ub.2 O     C, 64.89                                                      C, 64.81                                                 H,  8.25                                                      H,  8.07                                                 N, 10.81                                                      N, 10.67    25 +/-          2   H H         H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.16 H.sub.23 NO.sub.2.0.25H.sub.2                                      O          C, 72.28                                                      C, 72.01                                                 H,  8.91                                                      H,  8.84                                                 N,  5.27                                                      N,  5.22    26 +/-          2   H H         H CH.sub.2 CH(CH.sub.3).sub.2                                      C.sub.16 H.sub.23 NO.sub.2.0.1H.sub.2                                                 C, 73.02                                                      C, 72.92                                                 H,  8.89                                                      H,  8.95                                                 N,  5.32                                                      N,  5.22    27 +/-          2   Cl                H         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.20 NO.sub.2 Cl.0.1H.sub.2                                       O         C, 63.53                                                      C, 63.40                                                 H,  7.18                                                      H,  7.26                                                 N,  4.94                                                      N,  4.86    28 +/-          2   Cl                H         H NHCH.sub.2 CH.sub.3                                      C.sub.14 H.sub.19 N.sub.2 O.sub.2                                                 C, 59.46                                                      C, 59.47                                                 H,  6.77                                                      H,  6.69                                                 N,  9.91                                                      N,  9.76    29 +/-          2   Cl                H         H CH.sub.2 OCH.sub.3                                      C.sub.14 H.sub.18 NO.sub.3 Cl.0.5H.sub.2                                       O         C, 57.43                                                      C, 57.46                                                 H,  6.54                                                      H,  6.35                                                 N,  4.78                                                      N,  4.54    30 +/-          2   Cl                H         H CH(CH.sub.3).sub.2                                      C.sub.15 H.sub.20 NO.sub.2 Cl                                                 C, 63.94                                                      C, 63.66                                                 H,  7.15                                                      H,  7.12                                                 N,  4.97                                                      N,  4.82    31 +/ 4   H Br        H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.20 NO.sub.2 Br                                                 C, 55.22                                                      C, 55.28                                                 H,  6.18                                                      H,  6.27                                                 N,  4.29                                                      N,  4.22    32 -  4   H I         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.20 NO.sub.2 I                                                 C, 48.27                                                      C, 48.58                                                 H,  5.40                                                      H,  5.14                                                 N,  3.75                                                      N,  3.63    33 -  4   I H         H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.15 H.sub.20 NO.sub.2 I.0.1(H.sub.2                                       O)        C, 48.04                                                      C, 47.79                                                 H,  5.43                                                      H,  5.44                                                 N,  3.74                                                      N,  3.46    34 -  11  H 4(CF.sub.3)Ph                          H CH.sub.2 CH.sub.2 CH.sub.3                                      C.sub.22 H.sub.24 NO.sub.2 F.sub.3.0.75(                                      H.sub.2 O) C, 65.25                                                      C, 64.85                                                 H,  6.30                                                      H,  5.91                                                 N,  3.46                                                      N,  3.35    35 -  3   H H         H (CH.sub.2).sub.2 CH.sub.2 Cl                                      C.sub.15 H.sub.20 NO.sub.2 Cl                                                 C, 63.94                                                      C, 63.62                                                 H,  7.15                                                      H,  7.19                                                 N,  4.97                                                      N,  4.88    36 -  3   H H         H                             ##STR24##                                      C.sub.15 H.sub.19 NO.sub.2                                                 C, 73.44 H,  7.81 N,                                                      C, 73.23 H,  7.70 N,                                                      6.00    37 -  3   H H         H                             ##STR25##                                      C.sub.17 H.sub.23 NO.sub.2                                                 C, 74.69 H,  8.48 N,                                                      C, 74.61 H,  8.44 N,                                                      5.08    38 -  3   H H         H                             ##STR26##                                      C.sub.16 H.sub.21 NO.sub.2                                                 C, 74.10 H,  8.16 N,                                                      C, 74.04 H,  8.19 N,                                                      5.56    39 -  3   H H         H NHCH.sub.3                                      C.sub.13 H.sub.18 N.sub.2 O.sub.2                                                 C, 66.64                                                      C, 66.48                                                 H,  7.74                                                      H,  7.63                                                 N, 11.96                                                      N, 11.93    40 -  3   H H         H CH.sub.2 CH.sub.3                                      C.sub.14 H.sub.19 NO.sub.2                                                 C, 72.07                                                      C, 71.76                                                 H,  8.21                                                      H,  8.37                                                 N,  6.00                                                      N,  5.88    41 -  3   H H         H CH.sub.3  C.sub.13 H.sub.17 NO.sub.2.0.2(H.sub.2                                      O)         C, 70.05                                                      C, 70.05                                                 H,  7.87                                                      H,  7.79                                                 N,  6.28                                                      N,  6.35    42 -  3   H H         H CH.sub.2 CF.sub.3                                      C.sub.14 H.sub.16 NO.sub.2 F.sub.3                                                 C, 58.53                                                      C, 58.74                                                 H,  5.61                                                      H,  5.79                                                 N,  4.88                                                      N,  4.78    43 -  3   H H         H CH.sub.2 CH.sub.2 CF.sub.3                                      C.sub.15 H.sub.18 NO.sub.2 F.sub.3                                                 C, 59.79                                                      C, 60.02                                                 H,  6.02                                                      H,  6.26                                                 N,  4.65                                                      N,  4.58    __________________________________________________________________________

Table 2 gives chemical data for the Formula I compounds wherein R₁ and Rare hydrogen, G is methylene and R₂, X, Y, and Z are defined in thetable.

                                      TABLE 2    __________________________________________________________________________     ##STR27##    Ex.       Opt.          Prep.                                  Elemental analysis    No.       Ism.          Proc.             X           Y Z R.sub.2 Compound Formula                                                 Calc'd                                                      Found    __________________________________________________________________________     7a       ±          7,8             HO          H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.19 NO.sub.2.0.1H.sub.2                                                 C, 71.52                                                      C, 71.53                                                 H,  8.23                                                      H,  8.23                                                 N,  5.96                                                      N,  5.92     7b       ±          7  CH.sub.2CHCH.sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.17 H.sub.23 NO.sub.2.0.2H.sub.2                                                 C, 73.72                                                      C, 73.77                                                 H,  8.52                                                      H,  8.63                                                 N,  5.06                                                      N,  5.00     8 ±          8  (CH.sub.3).sub.2 CHO                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     CH.sub.17 H.sub.25 NO.sub.2                                                 C, 74.14                                                      C, 73.77                                                 H,  9.15                                                      H,  8.99                                                 N,  5.09                                                      N,  4.82    15 ±          15 HOCH.sub.2 CH.sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.16 H.sub.23 NO.sub.3                                                 C, 69.29                                                      C, 68.99                                                 H,  8.36                                                      H,  8.39                                                 N,  5.05                                                      N,  4.93    44 ±          3  F           H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.18 NOF                                                 C, 71.46                                                      C, 71.29                                                 H,  7.71                                                      H,  7.69                                                 N,  5.95                                                      N,  6.02    45 ±          7  Ph(CH.sub.2).sub.6O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.26 H.sub.35 NO.sub.2                                                 C, 79.35                                                      C, 78.95                                                 H,  8.96                                                      H,  9.24                                                 N,  3.56                                                      N,  3.53    46 ±          7  Ph(CH.sub.2).sub.7O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.27 H.sub.37 NO.sub.2                                                 C, 79.56                                                      C, 79.57                                                 H,  9.15                                                      H,  9.21                                                 N,  3.44                                                      N,  3.33    47 ±          7  PhCC(CH.sub.2).sub.3O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.25 H.sub.29 NO.sub.2.0.75H.sub.2                                                 C, 77.18                                                      C, 76.89                                                 H,  7.90                                                      H,  7.54                                                 N,  3.60                                                      N,  3.53    48 ±          7  CH.sub.3 CH.sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.16 H.sub.23 NO.sub.2                                                 C, 73.53                                                      C, 73.45                                                 H,  8.87                                                      H,  8.63                                                 N,  5.36                                                      N,  5.16    49 ±          7  CH.sub.3 (CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.17 H.sub.25 NO.sub.2                                                 C, 74.14                                                      C, 73.95                                                 H,  9.15                                                      H,  9.01                                                 N,  5.09                                                      N,  4.88    50 ±          7  CH.sub.3 (CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.18 H.sub.27 NO.sub.2                                                 C, 74.70                                                      C, 74.63                                                 H,  9.40                                                      H,  9.09                                                 N,  4.84                                                      N,  4.67    51 ±          7  CH.sub.3 (CH.sub.2).sub.4 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.19 H.sub.29 NO.sub.2                                                 C, 75.20                                                      C, 75.08                                                 H,  9.63                                                      H,  9.67                                                 N,  4.62                                                      N,  4.59    52 ±          7  CH.sub.3 (CH.sub.2).sub.5 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.20 H.sub.31 NO.sub.2                                                 C, 75.66                                                      C, 75.61                                                 H,  9.84                                                      H, 10.31                                                 N,  4.41                                                      N   4.41    53 ±          7  CH.sub.3 (CH.sub.2).sub.6 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.21 H.sub.33 NO.sub.2                                                 C, 76.09                                                      C, 75.94                                                 H, 10.03                                                      H,  9.99                                                 N,  4.23                                                      N,  4.19    54 ±          7  CH.sub.3 (CH.sub.2).sub.7 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.35 NO.sub.2                                                 C, 76.47                                                      C, 76.30                                                 H, 10.21                                                      H, 10.12                                                 N,  4.05                                                      N,  3.80    55 ±          7  CH.sub.3 (CH.sub.2).sub.8 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.37 NO.sub.2                                                 C, 76,83                                                      C, 77.73                                                 H, 10.37                                                      H, 10.33                                                 N,  3.90                                                      N,  3.78    56 ±          7  CH.sub.3 (CH.sub.2).sub.9 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.39 NO.sub.2                                                 C, 77.16                                                      C, 77.09                                                 H, 10.52                                                      N, 10.43                                                 N,  3.75                                                      N,  3.66    57 ±          7  CH.sub.3 (CH.sub.2).sub.10 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.25 H.sub.41 NO.sub.2                                                 C, 77.47                                                      C, 77.29                                                 H, 10.66                                                      H, 10.70                                                 N,  3.61                                                      N,  3.47    58 ±          7  CH.sub.3 (CH.sub.2).sub.11 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.26 H.sub.43 NO.sub.2                                                 C, 77.75                                                      C, 77.70                                                 H, 10.79                                                      H, 10.86                                                 N,  3.49                                                      N,  3.39    59 ±          7  CH.sub.3 (CH.sub.2).sub.15 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.30 H.sub.51 NO.sub.2                                                 C, 78.72                                                      C, 78.59                                                 H, 10.79                                                      H, 10.86                                                 N,  3.06                                                      N,  2.81    60 ±          7  PhCH.sub.2 CH.sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.27 NO.sub.2.0.25H.sub.2                                                 C, 77.27                                                      C, 77.40                                                 H,  8.11                                                      H,  8.02                                                 N,  4.10                                                      N,  3.70    61 ±          7  (CH.sub.3).sub.2 CHCH.sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.18 H.sub.27 NO.sub.2.0.1H.sub.2                                                 C, 74.24                                                      C, 74.22                                                 H,  9.42                                                      H,  9.28                                                 N,  4.81                                                      N,  4.49    62 ±          7  3(CH.sub.3 O)Ph(CH).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.31 NO.sub.3                                                 C, 75.56                                                      C, 75.21                                                 H,  8.19                                                      H,  8.15                                                 N,  3.67                                                      N,  3.53    63 ±          8  4-Pyridyl(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.28 N.sub.2 O.sub.2.0.25H.s                                     ub.2 O      C, 74.02                                                      C, 73.93                                                 H,  805                                                      H,  8.05                                                 N,  7.85                                                      N,  7.66    64 -  3  CF.sub.3 O  H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.18 NO.sub.2 F.sub.3                                                 C, 59.79                                                      C, 59.81                                                 H,  6.02                                                      H,  6.02                                                 N,  4.65                                                      N,  4.60    65 -  3  F           H H CH(CH.sub.3).sub.2                                     C.sub.14 H.sub.18 NOF                                                 C, 71.46                                                      C, 71.59                                                 H,  7.71                                                      H,  7.75                                                 N,  5.95                                                      N,  5.87    66 +  4  F           H Br                             CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.17 NOFBr                                                 C, 53.52                                                      C, 53.44                                                 H,  5.45                                                      H,  5.52                                                 N,  4.46                                                      N,  4.42    67 -  4  F           Br                           H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.17 NOFBr                                                 C, 53.52                                                      C, 53.69                                                 H,  5.45                                                      H,  5.56                                                 N,  4.46                                                      N,  4.43    68 -   4a             CF.sub.3 O  H I CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.17 NO.sub.2 F.sub.3                                                 C, 42.17                                                      C, 42.29                                                 H,  4.01                                                      H,  3.95                                                 N,  3.28                                                      N,  3.21    69 -   4a             CF.sub.3 O  I H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.17 NO.sub.2 F.sub.3                                                 C, 42.17                                                      C, 42.39                                                 H,  4.01                                                      H,  4.07                                                 N,  3.28                                                      N,  3.25    70 +   4a             F           H I CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.17 NOFI                                                 C, 46.55                                                      C, 46.57                                                 H,  4.74                                                      H,  4.68                                                 N,  3.88                                                      N,  3.85    71 -   4a             F           I H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.17 NO.sub.2 F.sub.3                                     I.0.1(EtOAc)                                                 C, 46.74                                                      C, 47.02                                                 H,  4.85                                                      H,  4.77                                                 N,  3.79                                                      N,  3.83    72 +   4a             CF.sub.3 O  H Br                             CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.17 NO.sub.2 F.sub.3                                                 C, 47.39                                                      C, 47.18                                                 H,  4.51                                                      H,  4.44                                                 N,  3.68                                                      N,  3.66    73 ±          2  Br          H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.18 NOBr.0.15(C.sub.6                                     H.sub.12)   C, 57.95                                                      C, 57.98                                                 H,  6.46                                                      H,  6.34                                                 N,  4.54                                                      N,  4.67    74 ±          2  Br          H H CH.sub.3                                     C.sub.12 H.sub.14 NOBr.0.1(C.sub.6                                     H.sub.12)   C, 54.72                                                      C, 54.85                                                 H,  5.54                                                      H,  5.49                                                 N,  5.10                                                      N,  5.13    75 ±          2  CH.sub.3    H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.21 NO.0.15(H.sub.2                                                 C, 76.98                                                      C, 76.86                                                 H,  9.17                                                      H,  9.08                                                 N,  5.99                                                      N,  6.35    76 ±          2  Br          H H CH.sub.2 CH.sub.3                                     C.sub.13 H.sub.16 NOBr.0.05(C.sub.6                                     H.sub.12)   C, 55.77                                                      C, 55.79                                                 H,  5.85                                                      H,  5.92                                                 N,  4.90                                                      N,  4.91    77 ±          2  CH.sub.3    H H CH(CH.sub.3).sub.2                                     C.sub.15 H.sub.21 NO                                                 C, 77.88                                                      C, 77.83                                                 H,  9.15                                                      H,  9.18                                                 N,  6.05                                                      N,  6.01    78 ±          2  CH.sub.3    H H CH.sub.3                                     C.sub.13 H.sub.17 NO.0.1(H.sub.2                                                 C, 76.13                                                      C, 75.76                                                 H,  8.45                                                      H,  8.37                                                 N,  6.82                                                      N,  6.43    79 -   7a             HO          H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.19 NO.sub.2 0.2(H.sub.2                                     O)          C, 70.97                                                      C, 71.04                                                 H,  8.26                                                      H,  8.22                                                 N,  5.91                                                      N,  5.69    80 ±          2  Cl          H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.18 NOCl.0.1(H.sub.2                                                 C, 66.31                                                      C, 66.53                                                 H,  7.24                                                      H,  7.40                                                 N,  5.52                                                      N,  5.45    81 ±          2  Cl          H H CH.sub.2 CH.sub.3                                     C.sub.13 H.sub.16 NOCl.0.1(H.sub.2                                                 C, 65.19                                                      C, 65.12                                                 H,  6.82                                                      H,  6.88                                                 N,  5.85                                                      N,  5.76    82 ±          2  Cl          H H CH.sub.3                                     C.sub.12 H.sub.14 NOCl.0.15(H.sub.2                                                 C, 63.66                                                      C, 63.43                                                 H,  6.46                                                      H,  6.53                                                 N,  6.19                                                      N,  6.15    83 ±          2  Cl          H H                              ##STR28##                                     C.sub.14 H.sub.16 NOCl                                                 C, 67.33 H,  6.46 N,                                                      C, 67.28 H,  6.60 N,                                                      5.43    84 -  7  3(CH.sub.3 O)Ph(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.31 NO.sub.3                                                 C, 75.56                                                      C, 75.36                                                 H,  8.19                                                      H,  8.22                                                 N,  3.67                                                      N,  3.59    85 ±          2  F           H F CH.sub.3                                     C.sub.12 H.sub.13 NOF.sub.2.0.25(H.sub.2                                     O)          C, 62.73                                                      C, 62.75                                                 H,  5.92                                                      H,  5.78                                                 N,  6.10                                                      N,  6.05    86 ±          2  F           H F CH.sub.2 CH.sub.3                                     C.sub.13 H.sub.15 NOF.sub.2.0.2(H.sub.2                                     O)          C, 64.29                                                      C, 64.22                                                 H,  6.39                                                      H,  6.14                                                 N,  5.77                                                      N,  5.72    87 ±          2  F           H F CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.17 NOF.sub.2.0.2(H.sub.2                                     O)          C, 65.45                                                      C, 65.61                                                 H,  6.83                                                      H,  6.59                                                 N,  5.45                                                      N,  5.39    88 ±          2  F           H F                              ##STR29##                                     C.sub.14 H.sub.15 NOF.sub.2                                                 C, 66.92 H,  6.02 N,                                                      C, 66.85 H,  6.08 N,                                                      5.57    89 -  3  CF.sub.2 CF.sub.3                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.16 H.sub.18 NOF.sub.5                                                 C, 57.31                                                      C, 57.26                                                 H,  5.41                                                      H,  5.57                                                 N,  4.18                                                      N,  4.17    90 -   3a             H           H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.19 NO.0.1(H.sub.2                                                 C, 76.38                                                      C, 76.87                                                 H,  8.83                                                      H,  8.94                                                 N,  6.45                                                      N,  6.39    91 ±           3a             H           H H CH.sub.3                                     C.sub.12 H.sub.15 NO                                                 C, 76.16                                                      C, 75.99                                                 H,  7.99                                                      H,  7.97                                                 N,  7.40                                                      N,  7.39    92 ±           3a             H           H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.14 H.sub.19 NO.0.2(H.sub.2                                                 C, 76.12                                                      C, 76.08                                                 H,  8.85                                                      H,  8.83                                                 N,  6.34                                                      N,  6.33    93 -  7  3(CH.sub.3 O)Ph(CH.sub.2).sub.3 O                         H I CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.30 NO.sub.3 I                                                 C, 56.81                                                      C, 57.02                                                 H,  5.96                                                      H,  6.03                                                 N,  2.76                                                      N,  2.71    94 ±          7  F(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.17 H.sub.24 NO.sub.2 F.0.25H.sub.2                                     O           C, 68.54                                                      C, 68.48                                                 H,  8.29                                                      H,  8.35                                                 N,  4.70                                                      N,  4.63    95 ±          7  Ph(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.29 NO.sub.2                                                 C, 78.60                                                      C, 78.32                                                 H,  8.32                                                      H,  8.39                                                 N,  3.98                                                      N,  3.85    96 ±          7  PhO(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.29 NO.sub.3                                                 C, 75.17                                                      C, 74.92                                                 H,  7.95                                                      H,  8.01                                                 N,  3.81                                                      N,  3.70    97 ±          7  PhO(CH.sub.2).sub.4 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.31 NO.sub.3                                                 C, 75.56                                                      C, 75.30                                                 H,  8.19                                                      H,  8.20                                                 N,  3.67                                                      N,  3.53    98 ±          7  1-Pyrryl(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.21 H.sub.28 N.sub.2 O.sub.2.0.25H.s                                     ub.2 O      C, 73.16                                                      C, 73.16                                                 H,  8.28                                                      H,  8.28                                                 N,  7.96                                                      N,  7.96    99 ±          7  (CH.sub.3).sub.2 CCH(CH.sub.2).sub.2                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.35 NO.sub.2                                                 C, 78.00                                                      C, 77.74             C(CH.sub.3)CHCH.sub.2 O             H,  9.55                                                      H,  9.60                                                 N,  3.79                                                      N,  3.55    100       ±          7  (CH.sub.3).sub.2 C(CH.sub.2).sub.4 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.21 H.sub.33 NO.sub.2.0.25H.sub.2                                                 C, 75.07                                                      C, 74.98                                                 H, 10.05                                                      H,  9.98                                                 N,  4.17                                                      N,  4.14    101       ±          7  (CH.sub.3).sub.2 CCH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.37 NO.sub.2.0.25H.sub.2                                                 C, 76.65                                                      C, 75.56             (CH.sub.2).sub.2 CH(CH.sub.3)       H, 10.05                                                      H, 10.04             CH.sub.2 CH.sub.2 O                 N,  3.73                                                      N,  3.66    102       ±          7  (CH.sub.3).sub.2 CCH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.37 NO.sub.2                                                 C, 77.58                                                      C, 77.40             (CH.sub.2).sub.2 CH(CH.sub.3)       H, 10.04                                                      H,  9.99             CH.sub.2 CH.sub.2 O                 N,  3.77                                                      N,  3.63    103       ±          7  (CH.sub.3).sub.2 CCH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.29 H.sub.43 NO.sub.2                                                 C, 79,59                                                      C, 79.25             (CH.sub.2).sub.2 C(CH.sub.3)        H,  9.90                                                      H,  9.92             CH(CH.sub.2).sub.2 C(CH.sub.3)CH    N,  3.20                                                      N,  3.02             CH.sub.2 O    104       ±          7  (CH.sub.3).sub.2 C(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.19 H.sub.29 NO.sub.2.0.25H.sub.2                                                 C, 74.10                                                      C, 74.07                                                 H,  9.66                                                      H,  9.51                                                 N,  4.55                                                      N,  4.44    105       ±          7  CH.sub.2 CH(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.19 H.sub.27 NO.sub.2.0.25H.sub.2                                                 C, 74.59                                                      C, 74.49                                                 H,  9.06                                                      H,  8.84                                                 N,  4.61                                                      N,  4.61    106       ±          7  (CH.sub.3).sub.2 CCH(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.20 H.sub.29 NO.sub.2.0.25H.sub.2                                                 C, 75.08                                                      C, 75.15                                                 H,  9.29                                                      H,  9.29                                                 N,  4.38                                                      N,  4.26    107       ±          7  NC(CH.sub.3).sub.2 C(CH.sub.2).sub.4 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.32 N.sub.2 O.sub.2.0.3H.su                                     b.2 O       C, 73.01                                                      C, 72.96                                                 H,  9.08                                                      H,  9.08                                                 N,  7.74                                                      N,  7.81    108       ±          7  CH.sub.3 O.sub.2 C(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.19 H.sub.27 NO.sub.4                                                 C, 73.01                                                      C, 72.96                                                 H,  9.08                                                      H,  9.08                                                 N,  7.74                                                      N,  7.81    109       ±          7  Ph(CH.sub.2).sub.4 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.31 NO.sub.2.0.25H.sub.2                                                 C, 77.90                                                      C, 77.89                                                 H,  8,58                                                      H,  8.47                                                 N,  3.79                                                      N,  3.70    110       ±          7  Ph(CH.sub.2).sub.5 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.25 H.sub.33 NO.sub.2.0.25H.sub.2                                                 C, 78.18                                                      C, 78.13                                                 H,  8,79                                                      H,  8.76                                                 N,  3.64                                                      N,  3.60    111       ±          7  CD.sub.3 O  H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.19 NO.sub.2 D.sub.3                                                 C, 70.59                                                      C, 70.20                                                 H,  8.48                                                      H,  8.43                                                 N,  5.56                                                      N,  5.39    112       ±          2  CH.sub.2 CH.sub.3                         H H CH.sub.3                                     C.sub.14 H.sub.19 NO                                                 C, 77.38                                                      C, 76.99                                                 H,  8.81                                                      H,  9.04                                                 N,  6.45                                                      N,  6.46    113       ±          2  CH.sub.2 CH.sub.3                         H H CH.sub.2 CH.sub.3                                     C.sub.15 H.sub.21 NO                                                 C, 77.88                                                      C, 77.55                                                 H,  9.15                                                      H,  9.39                                                 N,  6.05                                                      N,  5.99    114       ±          2  CH.sub.2 CH.sub.3                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.16 H.sub.23 NO                                                 C, 78.32                                                      C, 778.40                                                 H,  9.45                                                      H,  9.69                                                 N,  5.71                                                      N,  5.71    115       ±          2  CH.sub.2 CH.sub.3                         H H                              ##STR30##                                     C.sub.16 H.sub.21 NO                                                 C, 78.32 H,  9.45 H,                                                      C, 78.57 H,  8.86 N,                                                      5.68    116       ±          8  cyclohexyl(CH.sub.2).sub.4 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.37 NO.sub.2.0.1H.sub.2                                                 C, 77.21                                                      C, 76.96                                                 H, 10.04                                                      H, 10.27                                                 N,  3.75                                                      N,  3.93    117       ±          8  cyclohexyl(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.35 NO.sub.2.0.1H.sub.2                                                 C, 76.88                                                      C, 76.81                                                 H,  9.88                                                      H, 10.02                                                 N,  3.90                                                      N,  4.20    118       ±          8  CH.sub.3 CH.sub.2 (CH.sub.3)CH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.20 H.sub.31 NO.sub.2.0.25H.sub.2                                                 C, 74.61                                                      C, 74.22             (CH.sub.2).sub.2 O                  H,  9.86                                                      H,  9.82                                                 N,  4.35                                                      N,  4.62    119       ±          8  (CH.sub.3).sub.2 C(CH.sub.2).sub.3 CH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.39 NO.sub.2.0.1H.sub.2                                                 C, 76.79                                                      C, 76.70             (CH.sub.3)(CH.sub.2).sub.2 O        H, 10.53                                                      H, 10.89                                                 N,  3.73                                                      N,  3.81    120       ±          8  cyclopentyl(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.33 NO.sub.2.0.25H.sub.2                                                 C, 75.93                                                      C, 75.68                                                 H,  9.70                                                      H,  9.63                                                 N,  4.03                                                      N,  4.15    121       ±          8  (CH.sub.3).sub.3 CCH.sub.2 CH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.37 NO.sub.2                                                 C, 76.83                                                      C, 76.60             (CH.sub.3)CH.sub.2 CH.sub.2 O       H, 10.37                                                      H, 10.52                                                 N,  3.90                                                      N,  3.92    122       ±          8  HCCC(CH.sub.3)CH                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.20 H.sub.25 NO.sub.2.0.2(CH.sub.2                                     Cl.sub.2)   C, 74.07                                                      C, 74.24             CH.sub.2 O                          H,  7.55                                                      H,  7.74                                                 N,  4.60                                                      N,  4.23    123       ±          8  3(CF.sub.3)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.26 NO.sub.2 F.sub.3                                                 C, 68.13                                                      C, 67.89                                                 H,  6.46                                                      H,  6.51                                                 N,  3.45                                                      N,  3.55    124       ±          8  2(CF.sub.3)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.26 NO.sub.2 F.sub.3.0.1H.s                                     ub.2 O      C, 67.83                                                      C, 67.58                                                 H,  6.44                                                      H,  6.44                                                 N,  3.44                                                      N,  3.46    125       ±          8  3(F)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.26 NO.sub.2 F.0.25H.sub.2                                     O           C, 73.41                                                      C, 73.10                                                 H,  7.42                                                      H,  7.44                                                 N,  3.89                                                      N,  4.11    126       ±          8  2,6(CH(CH.sub.3).sub.2)Ph                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.28 H.sub.39 NO.sub.2.0.3H.sub.2                                                 C, 75.91                                                      C, 75.62             (CH.sub.2).sub.2 O                  H,  9.01                                                      H,  8.77                                                 N,  3.16                                                      N,  3.33    127       ±          8  4(CH.sub.3 O)Ph(CH.sub.2).sub.3 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.31 NO.sub.3.0.25H.sub.2                                                 C, 74.67                                                      C, 74.50                                                 H,  8.23                                                      H,  8.06                                                 N,  3.63                                                      N,  4.18    128       ±          8  2(F)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.26 NO.sub.2 F.0.55H.sub.2                                     O           C, 72.31                                                      C, 71.91                                                 H,  7.47                                                      H,  7.07                                                 N,  3.83                                                      N,  4.18    129       ±          8  3,4-(CH.sub.3 O)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.24 H.sub.31 NO.sub.4.0.2H.sub.2                                                 C, 71.86                                                      C, 71.86                                                 H,  7.89                                                      H,  7.82                                                 N,  3.49                                                      N,  3.49    130       ±          8  2(CH.sub.3 O)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.23 H.sub.29 NO.sub.3.0.2H.sub.2                                                 C, 74.44                                                      C, 74.22                                                 H,  7.98                                                      H,  7.70                                                 N,  3.78                                                      N,  3.44    131       ±          8  a           H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.27 H.sub.35 NO.sub.3.0.4H.sub.2                                                 C, 75.62                                                      C, 75.27                                                 H,  8.42                                                      H,  8.53                                                 N,  3.27                                                      N,  3.65    132       ±          8  b           H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.25 H.sub.31 NO.sub.3.0.6H.sub.2                                                 C, 74.26                                                      C, 73.90                                                 H,  8.03                                                      H,  7.73                                                 N,  3.49                                                      N,  3.89    133       ±          8  4(F)Ph(CH.sub.2).sub.2 O                         H H CH.sub.2 CH.sub.2 CH.sub.3                                     C.sub.22 H.sub.26 NO.sub.2 F.0.30H.sub.2                                     O           C, 73.22                                                      C, 72.94                                                 H,  7.43                                                      H,  7.44                                                 N,  3.88                                                      N,  4.26    __________________________________________________________________________     ##STR31##     ##STR32##

Table 3 shows chemical data for compounds of Formula I wherein X isOCH₃, Y and Z are H, and R₁ is H. The substituents R, G, and R₂ are asindicated in the table below.

                                      TABLE 3    __________________________________________________________________________     ##STR33##    Ex.       Opt.          Prep.                         Elemental analysis    No.       Ism.          Process              G    R  R.sub.2 Compound Formula                                        Calc'd                                             Found    __________________________________________________________________________     12       ±          12  CH.sub.2                   F  CH.sub.2 CH.sub.2 CH.sub.3                              C.sub.15 H.sub.19 F.sub.2 NO.sub.2                                        C, 63.59                                             C, 63.59                                        H,  6.76                                             H,  6.83                                        N,  4.94                                             N,  4.85     14       -  14  CHCH.sub.3                   H  CH.sub.2 CH.sub.2 CH.sub.3                              C.sub.16 H.sub.23 NO.sub.2                                        C, 73.53                                             C, 73.48              isomer A                  H,  8.87                                             H,  8.86                                        N,  5.36                                             N,  5.25     16       -  16  CH.sub.2 CH.sub.2                   H  CH.sub.2 CH.sub.2 CH.sub.3                              C.sub.16 H.sub.23 NO.sub.2.0.20H.sub.2 O                                        C, 72.53                                             C, 72.67                                        H,  8.90                                             H,  8.53                                        N,  5.29                                             N,  5.29     17       ±          17  CH.sub.2                   CH.sub.3                      CH.sub.2 CH.sub.2 CH.sub.3                              C.sub.17 H.sub.25 NO.sub.2                                        C, 74.14                                             C, 73.95                                        H,  9.15                                             H,  9.21                                        N,  5.09                                             N,  5.11    134       ±          12  CH.sub.2                   F  CH(CH.sub.3).sub.2                              C.sub.15 H.sub.19 F.sub.2 NO.sub.2                                        C, 63.59                                             C, 63.73                                        H,  6.76                                             H,  6.88                                        N,  4.94                                             N,  4.90    135       -  16  CH.sub.2 CH.sub.2                   H  CH.sub.2 CH.sub.3                              C.sub.15 H.sub.21 NO.sub.2                                        C, 72.84                                             C, 72.59                                        H,  8.56                                             H,  8.53                                        N,  5.66                                             N,  5.35    136       -  14  CHCH.sub.3                   H  CH.sub.2 CH.sub.2 CH.sub.3                              C.sub.16 H.sub.23 NO.sub.2                                        C, 73.53                                             C, 73.24              isomer B                  H,  8.87                                             H,  8.93                                        N,  5.36                                             N,  5.30    137       -  14  CHCH.sub.3                   H  CH.sub.2 CH.sub.3                              C.sub.15 H.sub.21 NO.sub.2                                        C, 72.84                                             C, 72.56              isomer A                  H,  8.56                                             H,  8.37                                        N,  5.66                                             N,  5.51    138       -  14  CHCH.sub.3                   H  CH.sub.2 CH.sub.3                              C.sub.15 H.sub.21 NO.sub.2                                        C, 72.84                                             C, 72.58              isomer B                  H,  8.56                                             H,  8.49                                        N,  5.66                                             N,  5.55    139       -  14  CHCH.sub.3                   H  CH.sub.3                              C.sub.14 H.sub.19 NO.sub.2                                        C, 72.07                                             C, 71.87              isomer B                  H,  8.21                                             H,  8.00                                        N,  6.00                                             N,  5.93    __________________________________________________________________________

Example 140 (Measurement of Melatonergic Binding)

The melatonergic binding of the compounds of Formula I was determined bya modification of the method of Reppert, S. M. et al. (Neuron, Volume13, pages 1177-1185, 1994). Compounds with IC₅₀ values of 600 nM or lessare termed active. The reagents, membranes, and other parameters used inthe assay are described below: Reagents:

(a) 50 mM Tris buffer containing 12.5 mM MgCl₂, and 2 mM EDTA (pH 7.4 at37° C.).

(b) Wash buffer: 20 mM Tris base containing 2 mM MgCl₂ (pH 7.4 at roomtemperature).

(c) 6-Chloromelatonin (10⁻⁵ M final concentration).

(d) 2- ¹²⁵ I!-Iodomelatonin (100 pM final concentration). (Source: NEN)

Membrane preparation: The cDNA (human ML_(1A)) in pcDNAI was introducedinto COS-1 cells by the DEAE-dextran method. Three days later, aftermedia removal, the plates were washed with buffered saline; the cellsremoved using Hank's balanced salt solution and pelleted. The supernantwas discarded and the pellets frozen. For membrane homogenates, thepellets were thawed and resuspended in TME buffer, Tris base, MgCl₂,EDTA (pH 7.4 at 37° C.), and supplemented with aprotinin, leupeptin, andphenylmethylsulfonyl fluoride. The cells were homogenized andcentrifuged; the resulting pellet resuspended in TME and frozen. Atassay, the small aliquot was thawed on ice and resuspended in TMEbuffer. Incubation: 37° C. for 1 hour. Reaction is terminated byfiltration.

Table 4 presents the melatonergic activity for Formula I compoundswherein X is OCH₃, R is hydrogen, G is methylene, and the othersubstituents are as indicated in the table.

                                      TABLE 4    __________________________________________________________________________     ##STR34##    Ex. Opt.    No.*        Ism.           Y  Z         R.sub.1                           R.sub.2   Binding**    __________________________________________________________________________    1   ±           H  F         H  CH(CH.sub.3).sub.2                                     ++    2   ±           H  H         H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++     3a +  H  H         H  CH.sub.2 CH.sub.2 CH.sub.3                                     +++     3b -  H  H         H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++    4   ±           H  I         H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++    5   -  Br Br        H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++    6   ±           H  H         Bn CH.sub.2 CH.sub.2 CH.sub.3                                     ++     9a +  H  PhCC      H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++     9b -  H  PhCH.sub.2 CH.sub.2                        H  CH.sub.2 CH.sub.2 CH.sub.3                                     +++    10  -  H  CN        H  CH.sub.2 CH.sub.2 CH.sub.3                                     +++    11  -  H  Ph        H  CH.sub.2 CH.sub.2 CH.sub.3                                     +++    13  -  H  NHCO(CH.sub.2).sub.2 CH.sub.3                        H  CH.sub.2 CH.sub.2 CH.sub.3                                     +    18  ±           H  H         H  CH.sub.2 CH.sub.3                                     ++++    19  ±           H  H         H  CH.sub.3  +++    20  ±           H  H         H  CH.sub.2 OCH.sub.3                                     +++    21  ±           H  H         H  CH(CH.sub.3).sub.2                                     +++    22  -  H  H         H  CH(CH.sub.3).sub.2                                     +++    25  ±           H  H         H  CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                     ++    27  ±           Cl H         H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++    32  -  H  I         H  CH.sub.2 CH.sub.2 CH.sub.3                                     ++++    33  -  I  H         H  CH.sub.2 CH.sub.2 CH.sub.3                                     +++    34  -  H  4(CF.sub.3)Ph                        H  CH.sub.2 CH.sub.2 CH.sub.3                                     +++    35  -  H  H         H  (CH.sub.2).sub.2 CH.sub.2 Cl                                     +++    36  -  H  H         H                            ##STR35##                                     ++++    37  -  H  H         H                            ##STR36##                                     +    39  -  H  H         H  NHCH.sub.3                                     ++++    41  -  H  H         H  CH.sub.3  ++++    42  -  H  H         H  CH.sub.2 CF.sub.3                                     ++++    __________________________________________________________________________     **Binding affinity (nM) at the human melatonin receptor as measured by     displacement of the reference compound (2 .sup.125 I!-Iodomelatonin) from     the receptor.     Affinities (IC.sub.50) reported fall into the following ranges:     + 250-600 nM,     ++ 40-250 nM,     +++ 5-40 nM, and     ++++ <5 nM.

Table 5 gives the melatonergic activity for the Formula I compoundswherein R₁ and R are hydrogen, G is methylene and R₂, X ,Y, and Z aredefined in the table.

                                      TABLE 5    __________________________________________________________________________     ##STR37##    Ex. Opt.    No. Ism.            X           Y  Z  R.sub.2 Binding**    __________________________________________________________________________     7a ±            HO          H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +     7b ±            CH.sub.2 CHCH.sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++     8  ±            (CH.sub.3).sub.2 CHO                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    15  ±            HOCH.sub.2 CH.sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    44  ±            F           H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    45  ±            Ph(CH.sub.2).sub.6 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    46  ±            Ph(CH.sub.2).sub.7 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    47  ±            PhCC(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +    48  ±            CH.sub.3 CH.sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    53  ±            CH.sub.3 (CH.sub.2).sub.6 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    54  ±            CH.sub.3 (CH.sub.2).sub.7 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    55  ±            CH.sub.3 (CH.sub.2).sub.8 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    56  ±            CH.sub.3 (CH.sub.2).sub.9 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    57  ±            CH.sub.3 (CH.sub.2).sub.10 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    58  ±            CH.sub.3 (CH.sub.2).sub.11 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    59  ±            CH.sub.3 (CH.sub.2).sub.15 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +    60  ±            PhCH.sub.2 CH.sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    61  ±            (CH.sub.3).sub.2 CHCH.sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +    62  ±            3(CH.sub.3 O)Ph(CH).sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    63  ±            4-Pyridyl(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    64  -   CF.sub.3 O  H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    65  -   F           H  H  CH(CH.sub.3).sub.2                                      +    66  +   F           H  Br CH.sub.2 CH.sub.2 CH.sub.3                                      +++    69  -   CF.sub.3 O  I  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    70  +   F           H  I  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    71  -   F           I  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    72  +   CF.sub.3 O  H  Br CH.sub.2 CH.sub.2 CH.sub.3                                      ++    73  ±            Br          H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    75  ±            CH.sub.3    H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    78  ±            CH.sub.3    H  H  CH.sub.3                                      ++    79  -   HO          H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    80  ±            Cl          H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    84  -   3(CH.sub.3 O)Ph(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++    87  ±            F           H  F  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    89  -   CF.sub.2 CF.sub.3                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    90  -   H           H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    93  -   3(CH.sub.3 O)Ph(CH.sub.2).sub.3 O                        H  I  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    94  ±            F(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    95  ±            Ph(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    96  ±            PhO(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    98  ±            1-Pyrryl(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    99  ±            (CH.sub.3).sub.2 CCH(CH.sub.2).sub.2                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++            C(CH.sub.3)CHCH.sub.2 O    100 ±            (CH.sub.3).sub.2 C(CH.sub.2).sub.4 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    103 ±            (CH.sub.3).sub.2 CCH                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++            (CH.sub.2).sub.2 C(CH.sub.3)            CH(CH.sub.2).sub.2 C(CH.sub.3)CH            CH.sub.2 O    105 ±            CH.sub.2 CH(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    106 ±            (CH.sub.3).sub.2 CCH(CH.sub.2).sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    107 ±            NC(CH.sub.3).sub.2 C(CH.sub.2).sub.4 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    108 ±            CH.sub.3 O.sub.2 C(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++    110 ±            Ph(CH.sub.2).sub.5 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++    111 ±            CD.sub.3 O  H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++    114 ±            CH.sub.2 CH.sub.3                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    116 ±            cyclohexyl(CH.sub.2).sub.4 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    120 ±            cyclopentyl(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++    121 ±            (CH.sub.3).sub.3 CCH.sub.2 CH                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++            (CH.sub.3)CH.sub.2 CH.sub.2 O    122 ±            HCCC(CH.sub.3)CH                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++            CH.sub.2 O    123 ±            3(CF.sub.3)Ph(CH.sub.2).sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++    125 ±            3(F)Ph(CH.sub.2).sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    127 ±            4(CH.sub.3 O)Ph(CH.sub.2).sub.3 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    128 ±            2(F)Ph(CH.sub.2).sub.2 O                        H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    131 ±            a           H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      +++    132 ±            b           H  H  CH.sub.2 CH.sub.2 CH.sub.3                                      ++++    __________________________________________________________________________     **Binding affinity (nM) at the human melatonin receptor as measured by     displacement of the reference compound (2 .sup.125 I!-Iodomelatonin) from     the receptor.     Affinities (IC.sub.50) reported fall into the following ranges:     + 250-600 nM,     ++ 40-250 nM,     +++ 5-40 nM, and     ++++ <5 nM.     ##STR38##     ##STR39##

Table 6 presents yhe melatonergic activity for compounds of Formula Iwherein X is OCH₃, Y and Z are H, and R₁ is H. The substituents R, G,and R₂ are as indicated in the table below.

                  TABLE 6    ______________________________________     ##STR40##    Ex.  Opt.    No.  Ism.     G         R     R.sub.2   Binding**    ______________________________________     12  +/-      CH.sub.2  F     CH.sub.2 CH.sub.2 CH.sub.3                                            ++++     14  -        CHMe      H     CH.sub.2 CH.sub.2 CH.sub.3                                            ++                  isomer A     16  -        CH.sub.2 CH.sub.2                            H     CH.sub.2 CH.sub.2 CH.sub.3                                            +     17  +/-      CH.sub.2  CH.sub.3                                  CH.sub.2 CH.sub.2 CH.sub.3                                            +    134  +/-      CH.sub.2  F     CH(CH.sub.3).sub.2                                            ++    136  -        CHMe      H     CH.sub.2 CH.sub.2 CH.sub.3                                            +++                  isomer B    ______________________________________     **Binding affinity (nM) at the human melatonin receptor as measured by     displacement of the reference compound (2 .sup.125 I!-Iodomelatonin) from     the receptor.     Affinities (IC.sub.50) reported fall into the following ranges:     + 250-600 nM,     ++ 40-250 nM,     +++ 5-40 nM, and     ++++ <5 nM.

Reasonable variations, such as those which would occur to a skilledartisan, can be made herein without departing from the scope of theinvention.

We claim:
 1. A melatonergic compound of Formula I ##STR41## wherein: Xis OR₅ wherein R₅ is C₇₋₂₀ pyridylalkyl or C₆₋₂₀ pyrrlalkyl;Y ishydrogen or halogen; Z is hydrogen, halogen, cyano, aryl, C₇₋₂₀ aralkyl,C₈₋₂₀ aralkynyl, or C₂₋₂₀ alkamido; R, in both cases, is hydrogen,halogen, or C₁₋₄ alkyl; G is a divalent methylene, ethylene, or C₁₋₄alylmethylene moiety; R₁ is hydrogen, C₁₋₄ alkyl or benzyl; and R₂ isC₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₄ alkoxyalkyl, C₁₋₄trifluoromethylalkyl or C₂₋₈ alkythioalkyl.
 2. A method of treating acircadian rhythm-related disorder in a patient in need of such treatmentcomprising administering to said patient a therapeutic amount of acompound of claim
 1. 3. A pharmaceutical composition for treatingcircadian rhythm-related disorders comprising a suitable amount of apharmaceutically acceptable carrier and a therapeutic amount of acompound of claim
 1. 4. The compound of claim 1 which is (trans)-N- 2-3- 3-(4-pyridinyl)propoxy!phenyl!cycloprop-1-yl!methyl!butanamide. 5.The compound of claim 1 which is (trans)-N- 2- 3-3-(1-pyrrolyl)propoxy!phenyl!cycloprop-1-yl!methyl!butanamide.